6-amino-1,4-hexahydro-1H-diazepine derivatives

ABSTRACT

Indazole-3-carboxylic acid derivatives represented by the following general formula (I) and their physiologically acceptable acid addition salts or quaternary ammonium salts, ##STR1## are useful as a potent and selective antagonist of serotonin 3 (5-HT 3 ) receptor. Also disclosed are compounds of the formula ##STR2## which are useful as intermediates in the production of the disclosed final product compounds.

This application is a division of application Ser. No. 384,766, filedJul. 25, 1989 (now U.S. Pat. No. 5,017,573).

This invention relates to a novel indazole-3-carboxylic acid derivativeuseful as a potent and selective antagonist of serotonin 3 (5-HT₃)receptor, processes for production thereof, a pharmaceutical compositioncomprising the above compound, and a novel intermediate for the abovecompound.

Since the development of4-amino-5-chloro-N-[(2-diethylamino)ethyl]-2-methoxybenzamide [genericname: metoclopramide; see, for example, Merck Index, 10th edition, 6019(1983)] in the mid-1960's as an antiemetic agent or a gastrointestinalmotility enhancing agent, various substituted benzamide derivatives andheteroaromatic carboxamide derivatives have been synthesized and theirpharmacological properties have been studied (for example, see JapaneseLaid-Open Patent Publications Nos. 83737/1977 and 123485/1985, and U.S.Pat. No. 4,207,327).

On the other hand, since the discovery in the late 1970's of MDL-72222(EP-A-67770) and ICS 205-930 (GB-A-2125398) which selectively antagonizeserotonin M receptor (now the serotonin M receptor is classified asserotonin 3 receptor), some serotonin 3 receptor antagonists have beendiscovered (for example, see EP-A-200444, EP-A-235878 and EP-A-247266).It was reported that these compounds are effective not only for nauseaand vomiting induced by anticancer agents, migraine and arrhythmia butalso for schizophrenia, anxiety neurosis and dependence on alcohol,nicotine and narcotics (GB-A-2206788).

The present inventors made extensive investigations in order to find anovel potent and selective serotonin 3 (5-HT₃ antagonist), and have nowfound that indazole-3-carboxylic acid derivatives of the followinggeneral formula (I), and physiologically acceptable acid addition saltsthereof and quaternary ammonium salts thereof have potent and selective5-HT₃ receptor antagonizing activity. ##STR3## wherein Y represents--NH-- or --O--;

R₁ and R₂ are identical or different and each represents a hydrogenatom, a lower alkyl group, a substituted lower alkyl group, a cycloalkylgroup, a lower alkenyl group, a cycloalkenyl group, a lower alkynylgroup, an unsubstituted or substituted aryl-lower alkyl group, a loweralkoxycarbonyl group, an unsubstituted or substituted aralkyloxycarbonylgroup or an acyl group, or R₁ and R₂, taken together, form a loweralkylene group;

R₃ represents a hydrogen atom, a lower alkyl group, or a phenyl group;

R₄ represents a hydrogen atom, a lower alkyl group, a substituted loweralkyl group, a cycloalkyl group, a lower alkenyl group, a cycloalkenylgroup, a lower alkynyl group, an unsubstituted or substituted aryl-loweralkyl group, a lower alkoxycarbonyl group, an unsubstituted orsubstituted aralkyloxycarbonyl group or an acyl group;

R₅ represents a hydrogen atom, a halogen atom, a lower alkyl group, alower alkoxy group, a hydroxyl group, a trifluoromethyl group, a nitrogroup, an amino group or an acylamino group;

m represents a number of 1, 2, 3 or 4;

n represents a number of 1, 2 or 3; and

p represents a number of 1, 2, 3 or 4.

The term "lower", as used in the present specification and the appendedclaims, unless otherwise specified, means that a group or a compoundqualified by this term has not more than 6, preferably not more than 4,carbon atoms.

The lower alkyl group, the lower alkenyl group, the lower alkynyl groupand the lower alkylene group in this invention may be linear orbranched. Specific examples of the lower alkyl group include methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, neopentyl, tert-pentyl, hexyl and isohexyl. The loweralkenyl group may contain 1 or 2 double bonds, preferably one doublebond. Specific examples of the lower alkenyl group include vinyl,propenyl, allyl, isopropenyl, butenyl. The lower alkynyl group maycontain 1 or 2 triple bonds, usually only one triple bond, in the mainchain, and its specific examples are propargyl, butan-3-ynyl,penten-4-ynyl and 2-penten-4-ynyl. The lower alkylene group includes,for example, methylene, trimethylene, propylene, tetramethylene,ethylethylene, pentamethylene and hexamethylene.

The lower alkoxy group and the lower alkoxycarbonyl group respectivelymean a (lower alkyl)--O-- group and a (lower alkyl)--O--CO-- group inwhich the lower alkyl moiety has the above meaning. Specific examples ofthe lower alkoxy group are methoxy, ethoxy, propoxy, butoxy, isopropoxy,pentyloxy and hexyloxy.

Specific examples of the lower alkoxycarbonyl group includemethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, pentyloxycarbonyl and hexyloxycarbonyl.

The cycloalkyl group includes saturated alicyclic groups having 3 to 8carbon atoms. Specific examples are cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The cycloalkenylgroup is preferably an unsaturated alicyclic group having 5 to 8 carbonatoms and containing 1 or 2 double bonds, usually 1 double bond in itsring, and specific examples are 2-cyclopenten-1-yl,2,4-cyclopentadien-1-yl, 1-cyclohexen-1-yl, 2-cyclohexen-1-yl,3-cyclohexen-1-yl, 2-cyclohepten-1-yl and 2-cycloocten-1-yl,

Examples of the halogen atom are fluorine, chlorine, bromine and iodineatoms.

The acyl moiety in the acyl group, the acylamino group and the acyloxygroup is an organic carboxylic acid residue, and can specifically be agroup represented by the following formula

    Q.sub.1 --CO--

wherein Q₁ represents a hydrogen atom, or an organic group, for examplea saturated or unsaturated, chain or cyclic aliphatic hydrocarbon group,an aromatic or araliphatic group which may be substituted by, forexample, halogen, lower alkyl, lower alkoxy, hydroxy, trifluoromethyl,cyano, amino or nitro, preferably a lower alkyl group, a lower alkenylgroup or an unsubstituted or substituted aryl group. Specific examplesof the acyl group include formyl, acetyl, propionyl, butyryl,isobutyryl, 2-methyl-2-phenoxyacetyl, acryloyl, methacryloyl, cinnamoyl,benzoyl, chlorobenzoyl, methylbenzoyl, methoxybenzoyl and nitrobenzoylgroups. In the substituted lower alkyl group, the substituent on thelower alkyl group may be, for example, a cycloalkyl group, acycloalkenyl group, a lower alkoxy group, a hydroxyl group, a cyanogroup, an oxo group (═O), an acyloxy group, an unsubstituted orsubstituted amino group, a heterocyclic group having 1 or 2 hetero atomsselected from oxygen, nitrogen and sulfur atoms, or a halogen atom. Theabove lower alkyl may be substituted by at least one, for example 1 to3, especially one, of these substituents. The unsubstituted orsubstituted amino group may include groups of the following formula##STR4## wherein Q₂ and Q₃ are identical or different, and eachrepresents a hydrogen atom, a lower alkyl group, an unsubstituted orsubstituted aryl-lower alkyl group, or an acyl group, or Q₂ and Q₃,taken together with the nitrogen atom to which they are bonded, may forma heterocyclic group which may further include a hetero atom selectedfrom nitrogen, oxygen and sulfur atoms. Specific examples of the aboveamino group include amino, methylamino, ethylamino, propylamino,isopropylamino, butylamino, tert-butylamino, dimethylamino,diethylamino, methylethylamino, methylpropylamino, benzylamino,(methoxybenzyl)amino, (nitrobenzyl)amino, methylbenzylamino,dibenzylamino, morpholino, 1-pyrrolidinyl, piperidino and4-methyl-1-piperazinyl groups.

The heterocyclic group having 1 or 2 hetero atoms selected from oxygen,nitrogen and sulfur atoms may be heteroalicyclic or heteroaromatic.Examples of the heteroalicyclic group include tetrahydrofuryl,tetrahydrothienyl, tetrahydropyranyl, 2- or 3-pyrrolidinyl, 2-, 3- or4-piperidinyl, 1,3-dioxolan-2-yl, 1,3- or 1,4-dioxocyclohexan-2-yl, 2-or 3-morpholinyl and 2-imidazolidinyl. The heteroaromatic group may bemonocyclic or polycyclic (condensed cyclic), and its examples are furyl,thienyl, oxazolyl, isoxazolyl, pyridyl, indolyl, benzisoxazolyl,quinolyl and isoquinolyl groups.

Thus, specific examples of the substituted lower alkyl groups include2-chloroethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-cyanoethyl,cyclopropylmethyl, 2-cyclopropylethyl, cyclohexylmethyl,1-(cyclohexen-1-yl)methyl, 2-(1-cyclohexen-1-yl)ethyl, 2-methoxyethyl,2-acetyloxyethyl, 3-aminopropoxy, 2-monoethylaminoethyl,2-dimethylaminoethyl, 3-benzoylaminopropyl, tetrahydrofurylmethyl,2-(2-tetrahydrofuryl)ethyl, 2-(3-tetrahydrofuryl)ethyl,2-tetrahydrothiophenylmethyl, 2-tetrahydropyranylmethyl,2-(1,3-dioxonyl)methyl, 2-(2-pyridyl)ethyl, 3-(1,3-dithioranyl)methyl,2-, 3-, or 4-pyridylmethyl, 2- or 3-furylmethyl, 3-thiophenylmethyl,3-benzisoxazolylmethyl and 2-quinolylmethyl.

The aryl in the unsubstituted or substituted aryl group may bemonocyclic or polycyclic, and includes, for example, phenyl andnaphthyl. The substituent on the aryl group may be, for example, ahalogen atom, a lower alkyl group, a fluoromethyl group, a hydroxylgroup, a lower alkoxy group, an unsubstituted or substituted aminogroup, a nitro group, a cyano group, a carboxyl group or a loweralkoxycarbonyl group. The aryl group may be substituted by 1 to 5,preferably 1 to 2, such substituents. Specific examples of thesubstituted aryl group include 2-, 3- or 4-methylphenyl, 2-, 3- or4-fluorophenyl, 2,4-, 2,5-, or 3,5-difluorophenyl,2,3,4,5,6pentafluorophenyl, 2-, 3- or 4-bromophenyl, 2-, 3- or4-chlorophenyl, 2-, 3-, or 4-cyanophenyl, 3-fluoro-5-cyanophenyl, 2-, 3-or 4-methoxyphenyl, 2-, 3- or 4-nitrophenyl, 2-, 3- or4-trifluoromethylphenyl, 2-, 3- or 4-aminophenyl, 2- 3- or4-methoxycarbonylphenyl and 2-(1-methyl)naphthyl.

The unsubstituted or substituted aryl-lower alkyl group is a lower alkylgroup substituted by the unsubstituted or substituted aryl group, inwhich the unsubstituted or substituted aryl moiety and the lower alkylmoiety in the unsubstituted or substituted aryl-lower alkyl group havethe above-mentioned meanings. Specific examples of the unsubstituted orsubstituted aryl-lower alkyl group include 2-, 3- or 4-methylbenzyl, 2-,3- or 4-fluorobenzyl, 2,4-, 2,5- or 3,5-difluorobenzyl,2,3,4,5,6-pentafluorobenzyl, 2-, 3- or 4-bromobenzyl, 2-, 3- or4-chlorobenzyl, 2-, 3- or 4-cyanobenzyl, 3-fluoro-5-cyanobenzyl, 2-, 3-or 4-nitrobenzyl, 2-, 3- or 4-trifluoromethylbenzyl, 2-, 3- or4-aminobenzyl, 2-phenylethyl, 1-phenylethyl and 1-phenyl-1-methylethyl.

The unsubstituted or substituted aralkyloxycarbonyl group is an(unsubstituted or substituted aryl-lower alkyl)--O--CO-- group, andincludes, for example, benzyloxycarbonyl, 2-, 3- or4-methylbenzyloxycarbonyl, 2-, 3- or 4-fluorobenzyloxycarbonyl, 2-, 3-or 4-bromobenzyloxycarbonyl, 2-, 3- or 4-chlorobenzyloxycarbonyl, 2-, 3-or 4-cyanobenzyloxycarbonyl, 2-, 3- or4-trifluoromethylbenzyloxycarbonyl, 2-phenylethyloxycarbonyl and1-phenylethyloxycarbonyl.

In general formula (I) above, Y is preferably --NH--, and n ispreferably 2.

A preferred group of compounds of general formula (I) are those ofgeneral formula (I) in which

R₁ represents a hydrogen atom or a lower alkyl group,

R₂ represents a hydrogen atom; a lower alkyl group; a lower alkyl groupsubstituted by C₃ -C₈ cycloalkyl, C₅ -C₈ cycloalkenyl, lower alkoxy,hydroxy, cyano, oxo, acyloxy, unsubstituted or substituted amino, aheterocyclic group having 1 to 2 hetero atoms selected from oxygen,nitrogen and sulfur atoms, or halogen; a C₃ -C₈ cycloalkyl group; alower alkenyl group; a C₅ -C₈ cycloalkenyl group; an aryl-lower alkylgroup which may optionally be substituted by halogen, lower alkyl,trifluoromethyl, hydroxy, lower alkoxy, unsubstituted or substitutedamino, nitro, cyano, carboxy, or lower alkoxycarbonyl; a loweralkoxycarbonyl group; an aralkyloxycarbonyl group; or an acyl group, orR₁ and R₂, taken together, represents a lower alkylene group,

R₃ represents a hydrogen atom, a lower alkyl group or a phenyl group,

R₄ represents a hydrogen atom; a lower alkyl group; a lower alkyl groupsubstituted by C₃ -C₈ cycloalkyl, C₅ -C₈ cycloalkenyl, lower alkoxy,hydroxy, cyano, oxo, acyloxy, substituted or unsubstituted amino, aheterocyclic group having 1 to 2 hetero atoms selected oxygen, nitrogenand sulfur, or halogen; a C₃ -C₈ cycloalkyl group; a lower alkenylgroup; a C₅ -C₈ cycloalkenyl group; an aryl-lower alkyl group which mayoptionally be substituted by halogen, lower alkyl, trifluoromethyl,hydroxy, lower alkoxy, unsubstituted or substituted amino, nitro, cyano,carboxy or lower alkoxycarbonyl; a lower alkoxycarbonyl group; anaralkyloxycarbonyl group; or an acyl group,

R₅ represents a hydrogen atom, a halogen atom, a lower alkyl group, ahydroxyl group, a lower alkoxy group or a trifluoromethyl group,

m is 1, and

p is 1 or 2.

A more preferred group of the compounds of formula (I) provided by thisinvention are compounds of the following general formula (I-1) ##STR5##wherein

R₁₁ represents a hydrogen atom or a lower alkyl group,

R₂₁ represents a hydrogen atom; a lower alkyl group; a lower alkyl groupsubstitutted by C₃ -C₆ cycloalkyl, C₅ -C₆ cycloalkenyl, or a 5- to6-membered heterocyclic group having 1 to 2 hetero atoms selected fromoxygen and nitrogen atoms; a C₃ -C₆ cycloalkyl group; an allyl group; ora phenyl-lower alkyl group which may optionally be substituted byhalogen, lower alkyl, trifluoromethyl, lower alkoxy, nitro or cyano,

R₃₁ represents a hydrogen atom or a lower alkyl group,

R₄₁ represents a hydrogen atom; a lower alkyl group; a lower alkyl groupsubstituted by C₃ -C₆ cycloalkyl, C₅ -C₆ cycloalkenyl, lower alkoxy,hydroxy or oxo; a C₃ -C₆ cycloalkyl group; an allyl group; an aryl-loweralkyl group which may optionally be substituted by halogen, lower alkyl,trifluoromethyl, hydroxy, lower alkoxy, unsubstituted or substitutedamino, nitro, cyano, carboxy or lower alkoxycarbonyl; a loweralkoxycarbonyl group; a lower alkanoyl group; or a benzoyl group,

R₅₁ represents a hydrogen atom, a halogen atom, a lower alkyl group or ahydroxyl group, and

p' is 1 or 2.

An especially preferred group of the compounds of this invention arethose of formula (I-2) below ##STR6## wherein

R₁₂ represents an alkyl group having 1 to 4 carbon atoms,

R₂₂ represents a hydrogen atom; a C₁ -C₄ alkyl group; a pyridylmethylgroup; or a benzyl group which may optionally be mono- or di-substitutedby halogen, C₁ -C₄ alkyl, trifluoromethyl, C₁ -C₄ alkoxy or cyano,

R₃₂ represents a hydrogen atom or an alkyl group having 1 to 4 carbonatoms,

R₄₂ represents a hydrogen atom, a C₁ -C₄ alkyl group, a hydroxyethylgroup, a 2-butanon-3-yl group, a cyclopropylmethyl group, an allylgroup, a C₅ -C₆ cycloalkyl group, a benzyl group, a C₂ -C₄alkoxycarbonyl group, a C₂ -C₄ alkanoyl group, or a benzoyl group, and

R₅₂ represents a hydrogen atom or a halogen atom.

It is especially preferred that in formula (I-2),

R₁₂ represent a methyl or ethyl group,

R₂₂ represent a methyl group, an ethyl group, a benzyl group, amethylbenzyl group, a fluorobenzyl group, a chlorobenzyl group, abromobenzyl group, a trifluoromethylbenzyl group, a methoxybenzyl group,a cyanobenzyl group, a difluorobenzyl group, a dimethylbenzyl group or apyridylmethyl group,

R₃₂ represent a hydrogen atom or a methyl group,

R₄₂ represent a hydrogen atom, a methyl group, an ethyl group, a propylgroup, a butyl group, a hydoxyethyl group, a allyl group, acyclopropylmethyl group, a cyclopentyl group, a benzyl group, an acetylgroup, a propionyl group, a benzoyl group, a 2-butanon-3-yl group, amethoxycarbonyl group, or an ethoxycarbonyl group, and

R₅₂ represents a hydrogen atom, a chlorine atom or a fluorine atom.

Specific examples of the compounds of this invention are given below.

N-[1-(3-methylbenzyl)-4-methylhexahydro-1H-1,4-diazepin-6-yl]-1-indazole-3-carboxamide,

N-[1-(4-methylbenzyl)-4-methylhexahydro-1H-1,4-diazepin-6-yl]-1H-indazole-3-carboxamide,

N-[1-(3-pyridylmethyl)-4-methylhexahydro-1H-1,4-diazepin-6-yl]-1H-indazole-3-carboxamide,

N-[1-(4-pyridylmethyl)-4-methylhexahydro-1H-1,4-diazepin-6-yl]-1H-indazole-3-carboxamide,

N-[1-(3-fluorobenzyl)-4-methylhexahydro-1H-1,4-diazepin-6-yl]-1H-indazole-3-carboxamide,

N-[1-(4-fluorobenzyl)-4-methylhexahydro-1H-1,4-diazepin-6-yl]-1H-indazole-3-carboxamide,

N-[1-(2-cyanobenzyl)-4-methylhexahydro-1H-1,4-diazepin-6-yl]-1H-indazole-3-carboxamide,

N-[1-(4-cyanobenzyl)-4-methylhexahydro-1H-1,4-diazepin-6-yl]-1H-indazole-3-carboxamide,

N-[1-(4-bromobenzyl)-4-methylhexahydro-1H-1,4-diazepin-6-yl]-1H-indazole-3-carboxamide,

N-[1-(3,5-difluorobenzyl)-4-methylhexahydro-1H-1,4-diazepin-6-yl]-1H-indazole-3-carboxamide,

N-(1-benzyl-2,4-dimethylhexahydro-1H-1,4-diazepin-6-yl)-1H-indazole-3-carboxamide,

N-(1-benzyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-1-methyl-1H-indazole-3-carboxamide,

N-(1-benzyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-1-acetyl-1H-indazole-3-carboxamide,

N-(1-benzyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-1-propionyl-1H-indazole-3-carboxamide,

N-[1-(3-fluoro-5-cyanobenzyl)-4-methylhexahydro-1H-1,4-diazepin-6-yl]-1H-indazole-3-carboxamide,

N-[1-(3,4-dibromobenzyl)-4-methylhexahydro-1H-1,4-diazepin-6-yl]-1H-indazole-3-carboxamide,

N-[1-(3-fluorobenzyl)-4-methylhexahydro-1H-1,4-diazepin-6-yl]-1-isobutyl-1H-indazole-3-carboxamide,

N-[1-(2-cyanobenzyl)-4-methylhexahydro-1H-1,4-diazepin-6-yl]-1-formyl-1H-indazole-3-carboxamide,

N-[1-(4-chlorobenzyl)-4-methylhexahydro-1H-1,4-diazepin-6-yl]-1-(2-propyonyl)-1H-indazole-3-carboxamide,

N-(1-furfuryl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-1H-indazole-3-carboxamide,

N-(1-thenyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-1H-indazole-3-carboxamide,

N-[1-(2-tetrahydrofurylmethyl)-4-methylhexahydro-1H-1,4-diazepin-6-yl]-1H-indazole-3-carboxamide,

N-(1-benzyl-4-ethylhexahydro-1H-1,4-diazepin-6-yl)-1H-indazole-3-carboxamide,and

(1-benzyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)1H-indazole-3-carboxylate.

The compounds of formula (I) provided by this invention can exist in theform of an acid addition salt or a quaternary ammonium salt. For examplethey may be inorganic acid salts such as hydrochlorides, hydrobromides,hydroiodides, sulfates and phosphates, or organic acid salts such asoxalates, maleates, fumarates malonates lactates, malates, citrates,tartrates, benzoates and methanesufonates. Examples of quatenaryammonium salts of the compounds of formula (I) are quaternary ammoniumsalts with lower alkyl halides such as methyl iodides, methylbromides,ethyliodides and ethylbromides, lower alkyl lower alkylsufonates such asmethyl methanesulfonate and ethyl methanesulfonate, and lower alkylarylsulfonates such as methyl p-toluenesulfonates. Of these,physiologically acceptable salts are preferred.

The comounds (I) of this invention may be produced by the followingprocesses.

Process (a)

In one aspect, the compound (I) of this invention can be produced byreacting a compound of the following general ##STR7## wherein R₄, R₅ andp are as defined, or its reactive derivative with a compound of thefollowing general formula (III) ##STR8## wherein Z₁ is --NH₂ or --OH,and R₁, R₂, R₃, n and m are as defined hereinabove, or its reactivederivative.

The reactive derivative of the compound of formula (II) may be, forexample, a lower alkyl ester, an activated ester, an acid anhydride, anacid halide (particularly an acid chloride) and a dimer of the compoundof formula (II) [see, for example, J. Org. Chem., 23,621 (1958)].Specific examples of the activated ester include a p-nitrophenyl ester,a 2,4,5-trichlorophenyl ester, a pentachlorophenyl ester, a cyanomethylester, an N-hydroxysuccinimide ester, an N-hydroxyphthalimide ester, a1-hydroxybenzotriazole ester, an N-hydroxy-5-norbornene2,3-dicarboximide ester, an N-hydroxypiperidine ester, an8-hydroxyquinoline ester, a 2-hydroxyphenyl ester, a2-hydroxy-4,5-dichlorophenyl ester, a 2-hydroxypyridine ester and a2-pyridylthiol ester. A symmetric mixed acid anhydride or a mixed acidanhydride may be used as the acid anhydride. Specific examples of themixed acid anhydride are mixed acid anhydrides with alkyl chloroformatessuch as ethyl chloroformate and isobutyl chloroformate, mixed acidanhydrides with aralkyl chloroformates such as benzyl chloroformate,mixed acid anhydrides with aryl chloroformates such as phenylchloroformate, and mixed acid anhydrides with alkanoic acids such asisovaleric acid and pivalic acid.

When the compound of formula (II) itself is used as the startingmaterial, the reaction may be carried out in the presence of acondensing agent such as dicyclohexyl carbodiimide,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride,N,N'-carbonyldiimidazole, N,N'-carbonyldisuccinimide,1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline and diphenylphosphorylazide.

Examples of the reactive derivative of a compound of formula (III) inwhich Z₁ is --OH are lithium salts or sodium salts of compounds offormula (III) in which Z₁ is --OH in the presence of strong bases suchas n-butyl lithium, lithium isopropylamine, or sodum hydride.

The reaction of the compound (II) or its reactive derivative with thecompound (III) or its reactive derivative is carried out in a solvent orin the absence of solvent. The solvent used should be properly selectedaccording to the types of the starting materials, for example. Examplesof the solvent include aromatic hydrocarbons such as benzene, tolueneand xylene, ethers such as diethyl ether, tetrahydrofuran and dioxane,halogenated hydrocarbons such as methylene chloride and chloroform,alcohols such as ethanol and isopropanol, ethyl acetate, acetone,acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, ethylene glycoland water. These solvents may be used singly or in combination with eachother. This reaction is carried out, as required, in the presence of abase. Specific examples of the base are alkali hydroxides such as sodiumhydroxide and potassium hydroxide, alkali bicarbonates such as sodiumbicarbonate and potassium bicarbonate, alkali carbonates such as sodiumcarbonate and potassium carbonate, and organic bases such astriethylamine, tributylamine, diisopropylethylamine andN-methylmorpholine. The compound (III) in which Z₁ is --NH₂ may be usedin an excessive amount to cause it serve concurrently as the base. Theproportion of the compound (III) used with respect to the compound (II)is not particularly limited. Generally, it is preferred to use thecompound (III) in an amount of 1 to 3 moles, especially 1 to 1.5 moles,per mole of the compound (II).

The reaction temperature varies with the types of the starting materialsused. Usually, it may be -30° C. to about 200° C., preferably about -10°C. to about 150° C. If the compound (II), its reactive derivative, thecompound (III), or its reactive derivative has in its structurefunctional groups, it is desirable to protect them in a customary mannerand eliminate the protecting groups after the reaction.

Process (b)

Compounds of formula (I) in which R₄ is as defined excepting hydrogenmay also be produced by reacting a compound of general formula (I-3)##STR9## wherein R₁, R₂, R₃, R₅, Y, m, n and p, with a compound of theformula (IV)

    X.sub.1 --R.sub.43                                         (IV)

wherein X₁ represents a residue of a reactive ester of an alcohol, andR₄₃ represents the groups defined for R₄ above except hydrogen.

The residue of the reactive ester of an alcohol represented by X₁ informula (IV) may be, for example, a halogen atom such as a chlorine,bromine or iodine atom, a lower alkylsulfonyloxy group such asmethansulfonyloxy and ethanesulfonyloxy, or an arylsulfonyloxy groupsuch as benzenesulfonyloxy and p-toluenesulfonyloxy. Where R₄₃ is anacyl group, an acid anhydride of a carboxylic acid corresponding to R₄₃may be used as compound (IV).

The reaction of the compound (I-3) with the compound (IV) is carried outusually in an appropriate solvent. Specific examples of the solventinclude aromatic hydrocarbons such as benzene, toluene and xylene,ketones such as acetone and methyl ethyl ketone, ethers such astetrahydrofuran and dioxane, alcohols such as ethanol and isopropylalcohol, acetonitrile, chloroform, ethyl acetate, N,N-dimethylformamideand dimethyl sulfoxide. These solvents may be used singly or incombination with each other. Desirably, this reaction is carried out inthe presence of a base. Specific examples of the base may be the same asthose described above with regard to process (a). When a compound offormula (IV) in which X₁ is chlorine or bromine is used, the addition ofan alkali metal iodide such as sodium iodide or potassium iodide enablesthe reaction to proceed smoothly.

The proportion of the compound of formula (IV) used relative to thecompound of formula (I-3) is not critical, and can be varied over abroad range. Generally, it is convenient to use the compound of formula(IV) in an amount of 1 to 5 moles, especially 1 to 2 mole, per mole ofthe compound of formula (I-3). The reaction temperature, which varieswith the types of the starting materials, for example, is usually about50° to about 200° C. If the compound (I-3) or the compound (IV) hasfunctional groups, it is desirable to protect them in a customary mannerand eliminate the protecting groups after the reaction.

Process (c)

Compounds of formula (I) in which R₁ and R₂ are as defined aboveexcepting hydrogen may also be produced by reacting a compound of thegeneral formula (I-4) ##STR10## wherein R₁, R₃, R₄, R₅, Y, m, n and pare as defined above, with a compound of the following formula (V)

    X.sub.2 --R.sub.23                                         (V)

wherein X₂ represents the same reactive ester residue as mentioned withregard to X₁, and R₂₃ represents the groups defined for R₂ exceptinghydrogen.

Usually, the reaction between the compound of formula (I-4) and thecompound of formula (V) may be carried out by using the same method andconditons as described above with regard to process (b). If R₂₃ informula (V) is an acyl group, an acid anhydride of a carboxylic acidcorresponding to R₂₃ may also be used as the compound (V). When thecompound of formula (I-4) or the compound of formula (V) has functionalgroups, it is desirable to protect them in a customary manner andeliminate the protecting groups after the reaction.

Process (d)

Compounds of formula (I) in which either one of R₁ and R₂ is a hydrogenatom or both R₁ and R₂ are hydrogen atoms may also be produced bycatalytically reducing a compound represented by the general formula(I-5) ##STR11## wherein R₁₃ represents an unsubstituted or substitutedbenzyl group, and R₂, R₃, R₄, R₅, Y, m, n and p are as defined above, inthe presence of a catalyst such as palladium-carbon, Raney-nickel orplatinum oxide in accordance with a method known per se, for example ina solvent.

The solvent may be those which are usually employed in catalyticreduction, such as alcohols (e.g., ethanol and methanol), water, andacetic acid. The reaction temperature is usually 0° to 80° C. When thecompound of formula (I-5) has functional groups, it is desirable toprotect them in a customary manner and eliminate the protecting groupsafter the reaction.

The compounds of formula (I) obtained by any of these processes may beisolated and purified by methods known per se, for example,chromatography, recrystallization, and reprecipitation.

Depending upon the selection of the starting compounds, the reaction andtreating conditions, etc., the compound of formula (I) may be obtainedin the form of a free base or an acid addition salt. The acid additionsalt may be converted to a free base by a conventional method, forexample, by treating it with a base such as an alkali carbonate or analkali hydroxide. The free base, on the other hand, may be converted toan acid addition salt by treatment with an acid in accordance with aconventional method.

The quaternary ammonium salt of the compound of formula (I) may beproduced by reacting the compound (I) with a compound composed of analkyl group or a benzyl group and an anionic component such as ahalogenide, a lower alkyl sulfate, a lower alkyl sulfonate, asubstituted or unsubstituted benzenesulfonate or a nitrate (e.g., methyliodide or benzyl bromide).

This reaction may be carried out by conventional methods in theproduction of quaternary ammonium salts, and the two compounds arereacted in a solvent or in the absence of solvent. Specific examples ofthe solvent include aromatic hydrocarbons such as benzene, toluene andxylene, ethers such as tetrahydrofuran and dioxane, dialkyl ketones suchas acetone, methyl ethyl ketone and methyl isobutyl ketone, loweralcohols such as methanol, ethanol and isopropyl alcohol, acetonitrile,N,N-dimethylformamide, and mixtures of these. The reaction temperature,which may vary with the types of the starting materials and the reactionsolvent, are usually about 10° to about 130° C., and the reaction timemay usually be 10 minutes to 72 hours.

The compounds of formula (III) used as the starting material in process(a) and their precursors of the following formula (III') ##STR12##wherein R₁, R₂, R₃, m and n are as defined above; and Z₂ represents--NR₆ R₇ or --OR₆ in which R₆ represents a hydrogen atom, a loweralkoxycarbonyl group, an unsubstituted or substituted aralkyloxycarbonylgroup or an acyl group, and R₇ represents a hydrogen atom, a loweralkoxycarbonyl group, an unsubstituted or substituted aralkyloxycarbonylgroup, an acyl group, a lower alkylsulfonyl group, an unsubstituted orsubstituted arylsulfonyl group or a trityl group, or R₆ and R₇, takentogether with the nitrogen atom to which they are bonded, may representa phthalimide group; provided that R₁ and R₂ do not simultaneouslyrepresent a benzyl group, are novel compounds not described in the priorliterature, and can be produced by the following processes.

Compounds of formula (III') in which R₆ and R₇ are as defined aboveexcepting hydrogen can be converted to compounds (III) in which R₆ andR₇ are hydrogen atoms usually by hydrolysis with acids or alkalies,catalytic reduction or reaction with hydrazine although the methodshould be properly selected depending upon the type of the compounds offormula (III').

Examples of the compounds of formula (III') in which R₆ and R₇ are otherthan hydrogen are

6-acetylamino-1-benzyl-4-methylhexahydro-1H-1,4-diazepine,

6-acetylamino-1-(3-methylbenzyl)-4-methylhexahydro-1H-1,4-diazepine,

6-acetylamino-1-(3-fluorobenzyl)-4-methylhexahydro-1H-1,4-diazepine,

6-acetylamino-1-(4-cyanobenzyl)-4-methylhexahydro-1H-1,4-diazepine,

6-acetylamino-1-(3-cyanobenzyl)-4-propylhexahydro-1H-1,4-diazepine,

6-acetylamino-1-(3,5-difluorobenzyl)-4-methylhexahydro-1H-1,4-diazepine,

6-acetylamino-1-(3-pyridylmethyl)-4-methylhexahydro-1H-1,4-diazepine,

6-acetylamino-1,4-dimethylhexahydro-1H-1,4-6-acetylamino-1,4-diethylhexahydro-1H-1,4-diazepine,

6-acetylamino-1,4-diethylhexahydro-1H-1,4-diazepine,

6-benzenesulfonylamino-1-benzyl-2,4-dimethylhexahydro-1H-1,4-diazepine,

6-benzyloxycarbonylamino-1-(3-methylbenzyl)-4-methylhexahydro-1H-1,4-diazepine,

6-ethoxycarbonylamino-1-benzyl-4-methylhexahydro-1H-1,4-diazepine,

6-(4-methylphenyl)sulfonylamino-1,4-dimethylhexahydro-1H-1,4-diazepine,and

N-(1-benzyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)phthalimide.

Since the compounds of formulae (I) and (III) have at least oneasymmetric carbon atom, their stereoisomers, mixtures thereof andracemic mixtures are embraced within the compounds of this invention.The compounds (I) may exist as hydrates and solvates which are alsoincluded within the compounds of this invention.

Process (1)

The compounds of formula (III') of this invention can be produced byreacting a compound of the general formula (VI) ##STR13## wherein m₁represents 1 or 2, R₁₄ and R₂₄ represent the groups defined above for R₁and R₂ excepting hydrogen, and R₃ and n are as defined above, or itsreactive derivative with a compound represented by the general formula(VII) ##STR14## wherein X₃ represents the same reactive ester residue asdescribed above for X₁, Z₃ represents the same groups defined above forZ₂ excepting --NH₂, R₃ and m are as defined above, m₂ represents 1 or 2and m₁ +m₂ =m, or its reactive equivalent of the following generalformula (VIIIa) or (VIIIb) ##STR15## wherein R₈ represents an arylgroup, X₄ represents the same reactive ester residue as described abovewith regard to X₁, R₇₁ represents the same groups defined above for R₇other than hydrogen, m₂ represents 1 or 2, the sum of m₁ +m₂ is 1, 2, 3or 4, and R₃ is as defined above.

The reactive derivative of the compound of formula (VI) may be, forexample, a lithium or sodium salt of the compound of formula (VI) in thepresence of a strong base such as n-butyllithium, lithiunisopropylamineor sodium hydride.

The reaction of the compound (VI) with the compound (VII), (VIIIa) of(VIIIb) is usually carried out in an appropriate solvent. Specificexamples of the solvent include aromatic hydrocarbons such as benzene,toluene and xylene, ketones such as acetone and methyl ethyl ketone,ethers such as tetrahydrofuran and dioxane, alcohols such as ethanol andisopropanol, acetonitrile, chloroform, ethyl acetate,N,N-dimethylformamide, dimethyl sulfoxide and water. These solvents maybe used singly or in combination with each other. This reaction ispreferably carried out in the presence of a base. Specific examples ofthe base may be the same as those given above with regard to process(a). When a compound of formula (VII), (VIIIa) or (VIIIb) in which X₃and X₄ are chlorine or bromine is used, the addition of an alkali metaliodide such as sodium iodide or potassium iodide enables the reaction toproceed smoothly.

The proportion of the compound (VII), (VIIIa) or (VIIIb) relative to thecompound (VI) is not particularly critical, and may be varied over abroad range. Generally, it is convenient to use the compound (VII),(VIIIa) or (VIIIb) in an amount of 1 to 5 moles, especially 1 to 2moles, per mole of the compound of formula (VI). The reactiontemperature, which differs depending upon the starting materials used,is usually about 10° to about 200° C. If the compound (VI), (VII),(VIIIa) or (VIIIb) has functional groups in its structure, it isdesirable to protect these groups in a customary manner, and eliminatethe protecting groups after the reaction.

Process (2)

Compounds of formula (III') in which Z₂ is --NH₂ can be produced byreacting a compound represented by the general formula (IX) ##STR16##wherein m₃ is 1, 2 or 3, R₁₅ and R₂₅ represent the same groups definedabove for R₁ and R₂ excepting hydrogen, X₅ represents the same reactiveester residue as defined above for X₁, and R₃ is as defined, providedthat R₃ is not bonded to the carbon to which --CH₂ X₅ is bonded, with anucleophilic agent such as sodium azide or potasium phthalimide, andthereafter, if sodium azide is used as the nucleophilic agent,catalytically reducing the resulting product using a catalyst such aspalladium-carbon, Raney-nickel or platinum oxide or reducing the productusing a reducing agent such as lithium aluminum hydride orbis(2-methoxyethoxy)aluminum hydride, and if potassium phthalimide isused as the nucleophilic agent, hydrolyzing the product with an acid ortreaing it with hydrazine.

The reaction of the compound of formula (IX) with sodium azide orpotassium phthalimide is carried out usually in an appropriate solvent.Specific examples of the solvent include aromatic hydrocarbons such asbenzene, toluene and xylene, ketones such as acetone and methylethylketone, ethers such as tetrahydrofuran and dioxane, alcohols suchas ethanol and isopropanol, acetonitrile, chloroform, ethyl acetate,N,N-dimethylformamide and dimethyl sulfoxide. These solvents may be usedsingly or in combination with each other.

The proportion of sodium azide or potassium phthalimide relative to thecompound of formula (IX) is not critical in particular, and can bevaried over a broad range. Generally, it is convenient to use 1 to 5moles, particularly 1 to 3 moles, of sodium azide or potassumphthalimide, per mole of the compound of formula (IX). The reactiontemperature, which varies with the types of the starting materials, isusually about 50° C. to about 200° C.

The catalytic reduction may be carried out in a solvent usually employedin catalytic reduction, for example an alcohol (e.g., ethanol ormethanol), water and acetic acid. Toluene and ethers such as diethylether and tetrahydrofuran may be used in the reaction with a reducingagent such as lithium aluminum hydride. These reducing reactions mayusually be carried out at 0° to 80° C.

The acid hydrolysis is carried out by using an inorganic acid such ashydrochloric acid and sulfuric acid. For example, alcohols (e.g.,methanol or ethanol), water, N,N-dimethylformamide and dimethylsulfoxide may be used as a solvent. The reaction with hydrazine iscarried out by usually employing an alcohol such as methanol or ethanolas a solvent. These reactions are carried out usually at 30° to 150° C.

When the compounds to be reacted have functional groups which mayparticipate in the reaction, it is necessary to choose a reaction inwhich these groups are not involved.

Process (3)

Compounds of formula (III') in which Z₂ is --NH₂ can be produced byreacting a compound represented by the general formula (X) ##STR17##wherein m₄ is 1 or 2, R₁₆ and R₂₆ represent the groups defined above forR₁ and R₂ excepting hydrogen, and R₃ and n are as defined above, withformalin and nitromethane, or tris(hydroxymethyl)nitromethane, theirequivalent to give a compound represented by the general formula (XI)##STR18## wherein m₄, n, R₁₆, R₂₆ and R₃ are as defined above,eliminating the formalin by the action of a base, and reducing theresulting compound of general formula (XII) ##STR19## wherein m₄, n,R₁₆, R₂₆ and R₃ are as defined above.

The reaction of the compound of formula (X) with formalin andnitromethane, or tris(hydroxymethyl)nitromethane is usually carried outin an appropriate solvent. Specific examples of the solvent includeketones such as acetone and methyl ethyl ketone, ethers such astetrahydrofuran and dioxane, alcohols such as ethanol and isopropanol,acetonitrile, chloroform, ethyl acetate, N,N-dimethylformamide, dimethylsulfoxide and water. These solvents are used singly or in combinationwith each other. This reaction is preferably carried out in the presenceof a base. Specific examples of the base may be the same as given abovewith regard to process (a).

The proportion of formalin and, nitromethane, ortris(hydroxymethyl)nitromethane relative to the compound of formula (X)is not particularly limited, and may be varied over a broad range.Generally, it is convenient to use 1 to 5 moles of nitromethane, 2 to 8moles of formalin and 1 to 5 moles of tris(hydroxymethyl)nitromethane,particualrly 1 to 2 moles of nitromethane, 2 to 3 moles of formalin and1 to 2 moles of tris(hydroxymethyl)nitromethane, per mole of thecompound of formula (X). The reaction temperature, which differsdepending upon the types of the starting materials, is usually about 10°to about 200° C.

The base used in the reaction of the compound of formula (XI) may be astrong base such as a sodium alkoxide, potassium tert-butoxide or sodiumhydride. The reaction is carried out in an appropriate solvent. Specificexamples of the solvent include aromatic hydrocarbons such as benzene,toluene and xylene, ethers such as tetrahydrofuran and dioxane, alcoholssuch as ethanol and isopropanol, acetonitrile, chloroform, ethylacetate, N,N-dimethylformamide and dimethyl sulfoxide. These solventsare used singly or in combination with each other.

The proportion of the strong base used relative to the compound offormula (XI) is not particularly limited, and can be varied over a broadrange. Generally, it is convenient to use 1 to 5 moles, especially 1 to2 moles, of the base, per mole of the compound of formula (X). Thereaction temperature differs depending upon the types of the startingmaterials. Usually, it is about 20 ° C. to about 100° C.

The catalytic reduction of the compound of formula (XII) and thereduction with a metal may be carried out in a customary manner.Solvents used in ordinary catalytic reduction, such as alcohols, (e.g.,ethanol or methanol), water and acetic acid, may be used in thecatalytic reduction. The reaction temperature differs with the types ofthe staring materials used, and is usually about 0° C. to about 80° C.If the compounds of formula (X), (XI) or (XII) has functional groups, itis desirable to protect them in a customary manner and eliminate theprotecting groups after the reaction.

Process (4)

Compounds of formula (III') in which one or both of R₁ and R₂ arehydrogen atoms can be produced by catalytically reducing a compoundrepresented by the following formula (III") ##STR20## wherein R₁₇represents an unsubstituted or substituted benzyl group, and R₂, Z₂, mand n are as defined above, in the presence of a catalyst such aspalladium-carbon, Raney-nickel or platinum oxide by an ordinary method.

Solvents usally employed in catalytic reduction, such as alcohols (e.g.,ethanol or methanol), water and acetic acid may be used in thiscatalytic reduction. The reaction temperature is usually 0° to 80° C. Ifthe compound of formula (III") has functional groups in its structure,it is desirable to protect them in a customary manner and eliminate theprotecting groups after the reaction.

The compounds of formula (I) provided by this invention have potent andselective serotonin 3 (5-HT₃) receptor antagonizing activity, and thepharmacological activities of typical examples of the compounds offormula (I) can be demonstrated by the following in vitro and in vivotests.

TEST 1 Effect on Von Bezold-Jarisch reflex in rats (Serotonin 3 receptorantagonist activity)

The test was carried out substantially by the method of Fozard et al.[cf. Arch. Pharmacology, 326, 36-44 (1984)]. Male Wistar rats weighing250-350 g or male SD rats weighing 300-400 g were anesthetized withurethane (1.5 g/kg, interraperitoneal) and placed on their back. Anelectrocardiogram (lead II) and a heart rate on the animals wererecorded on an inkwriting oscillograph via a biophysical amplifier and apulse rate tachomether, respectively. When 2-methylserotonin (5-HT₃agonist) at 10-30 μg/kg was administered intravenously, the heart ratewas transiently decreased (Von Bezold-Jarisch reflex). After stableresponses were obtained following repeated administration of2-methylserotonin at 15-minute intervals, the test compound (1 μg/kg)was administered intravenously 3 minutes before administration of2-methylserotonin. The inhibition rate of the test compound wascalculated as follows. ##EQU1## Inhibition rate are shown in Table 1.

                  TABLE 1                                                         ______________________________________                                        Effect on Von Bezold-Jarisch reflex in rats                                   Test      Inhibition   Test      Inhibition                                   compound  rate (%)     compound  rate (%)                                     ______________________________________                                         1(a)*    82           16        85                                            1(b)     83           17        91                                            3        92           23        86                                            5        78           33        96                                            6        75           46        70                                            7        84           48        79                                            8        77           52        89                                           10        82           53        83                                           11        95           67        72                                           13        83           69        90                                           ______________________________________                                         *)Compound of Example 1 (a) (herinafter, the same)                       

TEST 2 Effect on cisplatin-induced vomiting in ferrets and acutetoxicity in mice

Male ferrets (Marshall Lab., U.S.A.) weighing approximately 1 kg wereused. For intravenous injection, a cannule was implanted in the cervicalvein under pentobarbital anethesia. The experiments were started 3 and 4days after the operation. Saline (2 ml/kg) as a control group and a dose(0.03 mg/kg) of a test compound as a treated group were administeredtwice, i.e., 30 minutes before and 45 minutes after administratin of 10mg/kg of cisplatin (Sigma, U.S.A) dissolved in saline (3 ml/kg). Thenumber of emetic episodes for 3 hours after administration of cisplatinwas recorded, and the inhibition rate of the test compound wascalculated as follows. ##EQU2##

All test compounds were administered intravenously.

An acute toxicity test was performed using male Std-ddY mice weighing25-30 g. Test compounds dissolved or suspended in 0.5% tragacanthsolution were administered intraperitoneally. The mortality was observedfor 7 days after the administration.

The results are shown in Table 2.

                  TABLE 2                                                         ______________________________________                                        Effect on cisplatin-induced vomiting in ferrets                               and acute toxicity in mice                                                                               Acute                                                                         toxicity                                                        Inhibition of emetic                                                                        in mice                                                         episodes in ferrets                                                                         [dose:                                             Test         Inhibition rate                                                                             100 mg/kg                                          compound     (%)           (i.p.)]                                            ______________________________________                                         1(a)*       89             1/5**                                              8           71            0/5                                                16           82            0/5                                                17           62            1/5                                                32           62            0/5                                                33           44            2/5                                                53           29            1/5                                                ______________________________________                                         *)The compound of Example 1 (a)                                               **)the number of dead animals/the number of animals used                 

As can be seen from the test results given above, the compounds offormula (I) and their physiologically acceptable acid addition salts andquaternary ammonium salts have potent serotonin 3 (5-HT₃) receptorantagonizing activity, and can be used for the treatment and preventionof various diseases induced by stimulation of serotonin 3 (5-HT₃)receptor, for example the treatment and prevention of anorexia, nausea,vomiting and abdominal discomfort in acute and chronic gastritis,gastric and duodenal ulcer, gastric neurosis, and gastroptosis: And ofesophageal and biliary duct disorders, urinary tract disorders anddiarrhaea and constipation in irritable bowel syndrome or carcinoidsyndrome. They can also be used for the treatment and prevention ofnausea and vomiting following administration of anticancer agents suchas cisplatin and X-ray irradiation, and motion sickness such ascarsickness, seasickness and airsickness; cluster headache, migraine andtrigeminal neuralgia; and the treatment of psychotic disorders such asanxiety, agonia, schizophrenia and mania, dementia, sensory disturbance,stress-related psychiatric disorders, cardiac disorders (such asarrhythmia and angina pectoris), obesity, lung embolism, rhinitis,seroton-induced rhinophathia, somolence, and pain. They can also be usedto treat and prevent intoxication by addictive drugs such as morphine,nicotine and amphetamine.

They may be administered orally, parenterally or intrarectally. Theclinical dose of the compound of formula (I) or its physiologicallyacceptable salt or quaternary ammonium salt varies with the type of thecompound, the administration route, the severity of the disease, the ageof the patient, etc. Usually, it is 0.0001 to 20 mg/kg/day, preferably0.001 to 5 mg/kg/day.

The compound of formula (I) or its salt is usually administered in theform of a pharmaceutical composition prepared by admixing withpharmaceutically acceptable carriers. The pharmaceutical carriers may bethose substances which are ordinarily used in the pharmaceutical fieldand do not react with the compound of formula (I) or its salt. Specificexamples include ciric acid, glutaic acid, glycine, lactose, inositol,glucose, mannitol, dextrin, sorbitol, cyclodextrin, starch, sucrose,methyl p-hydroxybenzoate, magnesium aluminosilicate tetrahydrate,synthetic aluminum silicate, microcrystalline cellulose, sodiumcarboxymethylcellulose, hydroxypropyl starch, calciumcarboxymethylcellulose, ion-exchange resins, methyl cellulose, gelatin,acacia, pullulan, hydroxypropylcellulose, hydroxypropylcellulose of alow degree of substitution, hydroxy propylmethylcellulose,polyvinylpyrrolidone, polyvinyl alcohol, light sillicic anhydride,magnesium stearate, talc, tragacanth, bentonite, veegum, carboxyvinylpolymer, titanium dioxide, sodium chloride, sorbitan fatty acid esters,sodium laurylsulfate, glycerol, fatty acid glycerides, purified lanolin,glycerogelatin, polysorbate, macrogol, vegetable oils, waxes, propyleneglycol, ethanol, benzyl alcohol, sodium hydroxide and hydrochloric acid.The dosage forms of the pharmaceutical composition include tablets,capsules, granules, fine granules, powder, syrups, suspensions,injections, and suppositories. They are prepared by conventionalmethods. Liquid preparations may be dissolved or suspended in water orother suitable media before use. Tablets, granules and fine granules maybe coated by known methods. These preparations may contain one or moreother therapeuticaly active compounds.

The following Reference Examples and Examples illustrate the presentinvention more specifically. The invention should not be construed to belimited to these examples. In these examples, the compounds wereidentified by elemental analysis, mass spectrum, IR spectrum, UVspectrum, NMR spectrum, etc.

For simplification, the following abbreviations are sometmes used inthese examples.

A: ethanol

AC: acetone

E: diethyl ether

M: methanol

Me: methyl group

Et: ethyl group

Ph: phenyl group

J: coupling constant

s: singlet

d: doublet

dd: double doublet

t: triplet

q: quartet

quint: quintet

m: multiplet

br: broad

q.s.: quantum sufficit

REFERENCE EXAMPLE 1

Preparation of 6-fluoro-1H-indazole-3-carboxylic acid:

6-Fluoroisatin prepared according to the method of J. Org. Chem., 21,169 (1956) is added to a solution of sodium hydroxide (7.4 g) in water(130 ml), and the mixture obtained is gently heated until it dissolves.

After the solution is cooled to 0° C., a solution of sodium nitrite(13.8 g) in water (45 ml) is added dropwise to the reaction mixture, andthis mixture is poured, in small portions with vigorous stirring, intothe sulfuric acid (33.9 g) in water (430 ml) at 0° C. The mixture isstirred for 30 minutes at 0° C. A solution of stannous chloride (85.3 g)in hydrochloric acid (170 ml) is added dropwise to the reaction mixtureat 0° C., and the mixture is stirred at 25° C. for 2 hours. Theprecipitates are collected and washed successively with water, acetone,and methanol, and dried to give the title compound (15.6 g), m.p. >290°C. Mass spectrum: m/z 180.

Various compounds of Reference Example 2 to 5 are prepared insubstantially the same manner as in Reference Example 1, using thecorresponding starting materials in place of 6-fluoroisatine.

REFERENCE EXAMPLE 2

4-chloro-1H-indazole-3-carboxylic acid. Mass spectrum: m/z 196.

REFERENCE EXAMPLE 3

6-chloro-1H-indazole-3-carboxylic acid. Mass spectrum: m/z 196.

REFERENCE EXAMPLE 4

7-chloro-1H-indazole-3-carboxylic acid, m.p. 243°-245° C.

REFERENCE EXAMPLE 5

5,6-difluoro-1H-indazole-3-carboxylic acid, m.p. 288°-293° C.

EXAMPLE 1 Preparation ofN-[1-(3-methylbenzyl)-4-methylhexahydro-1H-1,4-diazepin-6-yl]-1H-indazole-3-carboxamide

A solution of6-acetylamino-1-(3-methylbenzyl)-4-methyl-hexahydro-1H-1,4-diazepine(0.9 g) in 10% hydrochloric acid (20 ml) is refluxed with stirring for 2hours. After cooling, the reaction mixture is basified with 48% aqueoussodium hydroxide solution and extracted with chloroform. The organiclayer is washed with water and dried over magnesium sulfate. The solventis evaporated under reduced pressure to give an oil. A mixture of thisoil, 1H-indazole-3-carboxylic acid (530 mg),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (630 mg) anddichloromethane (20 ml) is stirred at 25° C. for 2 hours. The reactionmixture is washed successively with water and 10% aqueous sodiumhydroxide solution, dried over magnesium sulfate, and evaporated underreduced pressure. The residue is chromatographed on silica gel withelution of acetone. Fractions containing the title compound are pooledand evaporated under reduced pressure to give the title compound (0.4 g)as an oil.

(a) The free base thus obtained is converted to the hemifumarate of thetitle compound in a usual manner, m.p. 190°-192° C. (recrystallized fromethanol).

¹ H-NMR spectrum (DMSO-D₆, δppm): 2.20 (3H, s, --CH₂ C₆ H₄ CH₃), 2.41(3H, s, --NCH₃), 2.5-3.1 (8H, m), 3.63 (2H, s, --NCH₂ C₆ H₄ CH₃),3.9-4.4 (1H, m, --CONHCH--), 6.8-7.7 (7H, m), 8.16 (each 1H, each d,each J=8Hz, --CONH--, 4-H), 13-14 (1H, br s, --NH).

(b) The free base obtained above is converted to the dihydrochloride ofthe title compound in a usual manner, m.p. 241°-244° C. (recrystallizedfrom methanol-water).

EXAMPLE 2-26

Various compounds listed in the following Table 3 are prepared insubstantially the same manner as in Example 1, using1H-indazole-3-carboxylic acid and the corresponding6-acetylamino-1-methylhexahydro-1H-1,4-diazepine derivatives.

                  TABLE 3                                                         ______________________________________                                         ##STR21##                                                                                                    m.p.   Recry.                                 Ex.  R.sub.2           Q        (°C.)                                                                         solv.                                  ______________________________________                                         2                                                                                  ##STR22##        oxalate. H.sub.2 O                                                                     103˜106                                                                        A-E                                     3                                                                                  ##STR23##        hemi- fumarate                                                                         234˜237                                                                        A                                       4                                                                                  ##STR24##        hemi- fumarate. 1/4H.sub.2 O                                                           230˜231                                                                        A                                       5                                                                                  ##STR25##        hemi- fumarate                                                                         196˜198                                                                        A                                       6                                                                                  ##STR26##        oxalate. 3/4H.sub.2 O                                                                   87˜ 90                                                                        A-E                                     7                                                                                  ##STR27##        hemi- fumarate                                                                         169˜171                                                                        A                                       8                                                                                  ##STR28##        hemi- fumarate                                                                         205˜207                                                                        A                                       9                                                                                  ##STR29##        hemi- fumarate. 1/5H.sub.2 O                                                           243˜246                                                                        M                                      10                                                                                  ##STR30##        hemi- fumarate                                                                         241˜244                                                                        M                                      11                                                                                  ##STR31##        oxalate. 1/4H.sub.2 O                                                                  102˜107                                                                        A-E                                    12                                                                                  ##STR32##        fumarate. 1/4H.sub.2 O                                                                 159˜161                                                                        A-AC                                   13                                                                                  ##STR33##        hemi- fumarate. 1/4H.sub.2 O                                                           214˜216                                                                        M                                      14                                                                                  ##STR34##        hemi- fumarate. 1/4EtOH                                                                199˜202                                                                        A                                      15                                                                                  ##STR35##        sesqui- oxalate. 7/4H.sub.2 O                                                           95˜100                                                                        A-E                                    16                                                                                  ##STR36##        5/2 fumarate                                                                           170˜172                                                                        A                                      17                                                                                  ##STR37##        di- fumarate. 1/2H.sub.2 O                                                              80˜85                                                                         A-E                                    18                                                                                  ##STR38##        oxalate. 5/4H.sub.2 O                                                                   98˜101                                                                        A-E                                    19                                                                                  ##STR39##        sesqui- oxalate. 1/2H.sub.2 O                                                           99˜102                                                                        A-E                                    20   CH.sub.2 CHCH.sub.2                                                                             sesqui-   85˜88                                                                         A-E                                                           oxalate.                                                                      1/2H.sub.2 O                                           21                                                                                  ##STR40##        dioxalate. 3/4H.sub.2 O                                                                118˜121                                                                        A                                      22                                                                                  ##STR41##        hemi- fumarate.                                                                        177˜178                                                                        A                                      23                                                                                  ##STR42##        fumarate. 3/4H.sub.2 O                                                                 129˜131                                                                        A                                      24                                                                                  ##STR43##         --      184˜185                                                                        AC                                     25                                                                                  ##STR44##        dioxalate. 1/4H.sub.2 O                                                                109˜111                                                                        A-E                                    26                                                                                  ##STR45##        sesqui- oxalate. 1/2H.sub.2 O                                                          103˜105                                                                        A-E                                    ______________________________________                                    

EXAMPLE 27 Preparation ofN-[1-(2,5-dimethylbenzyl)-4-methylhexahydro-1H-1,4-diazepin-6-yl]-1H-indazole-3-carboxamide

To a solution of 1H-indazole-3-carboxylic acid (1.0 g) inN,N-dimethylformamide (20 ml), N,N'-carbonyldiimidazole (1.1 g) isadded, and the mixture is heated at 60° C. for 2 hours.6-Amino-1-(2,5-dimethylbenzyl)-4-methylhexahydro-1H-1,4-diazepine (1.5g) is added to the reaction mixture, and the mixture is heated at 60° C.for 2 hours. The solvent is evaporated under reduced pressure, and theresidue is diluted with water and extracted with chloroform. The organiclayer is washed successively with water and aqueous sodium hydroxidesolution, and dried over sodium sulfate. The solvent is evaporated underreduced pressure, and the residue is chromatographed on silica gel withelution of acetone. Fractions containing the title compound are pooledand evaporated under reduced pressure to give the title compound (1.6 g)as an oil. The free base thus obtained is converted to the fumarate ofthe title compound in a usual manner, m.p. 168°-170° C. (recrystallizedfrom ethanol).

¹ H-NMR spectrum (DMSO-D₆, δppm): 2.15, 2.30 [each 3H, each s, --CH₂ C₆H₃ (CH₃)₂ ], 2.40 (3H, s, --NCH₃), 3.50 [2H, s, --NCH₂ C₆ H₃ (CH₃)₂ ],4.2 (1H, m, --CONHCH--), 6.7-7.7 (5H, m), 8.03 (1H, d, J=8Hz, --CONH--),8.14 (1H, d, J=8Hz, 4-H), 11.5 (1H, br s, --NH).

EXAMPLE 28 Preparation ofN-(1,4-dimethylhexahydro-1H-1,4-diazepin-6-yl)-1H-indazole-3-carboxamide

Difumarate 1/4 hydrate of the title compound is prepared insubstantially the same manner as in Example 27, using6-amino-1,4-dimethylhexahydro-1H-1,4-diazepine in place of6-amino-1-(2,5-dimethylbenzyl)-4-methylhexahydro-1H-1,4-diazepine inExample 27, m.p. 153°-155° C. (recrystallized from ethanol).

¹ H-NMR spectrum (DMSO-D₆, δppm): 2.43 [6H, s, 2(--NCH₃)], 2.6-3.1 (8H,m), 4.34 (1H, m, --CONHCH--), 7.1-7.8 (3H, m, 5-H, 6-H, 7-H), 8.0-8.4(2H, m, --CONH--, 4-H).

EXAMPLE 29 Preparation ofN-(1,4-dibenzylhexahydro-1H-1,4-diazepin-6-yl)-1H-indazole-3-carboxamide

The title compound is prepared in substantially the same manner as inExample 1, using 6-acetylamino-1,4-dibenzylhexahydro-1H-1,4-diazepine inplace of6-acetylamino-1-(3-methylbenzyl)-4-methylhexahydro-1H-1,4-diazepine inExample 1, m.p. 115°-116° C. (recrystallized from ethanol).

¹ H-NMR spectrum (DMSO-D₆, δppm): 2.4-2.9 (4H, m), 3.00[4H, t, J=4Hz,2(--NCH₂ --)], 3.67 [4H, s, 2(--NCH₂ Ph)], 4.2-4.7 (1H, m, --CONHCH--),7.0-7.5 [13H, m, 5-H, 6-H, 7-H, 2(--CH₂ C₆ H₅)], 8.36 (1H, d, J=9Hz,4-H), 8.50 (1H, d, J=9Hz, --CONH--), 11-13 (1H, br s, --NH).

EXAMPLE 30 Preparation ofN-(1-methylhexahydro-1H-1,4-diazepin-6-yl)-1H-indazole-3-carboxamide

N-(1-Benzyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-1H-indazole-3-carboxamide(850 mg) is dissolved in ethanol (40 ml) and hydrogenated over 10%palladium on carbon (100 mg) at about 50° C. After the calculated amountof the hydrogen is absorbed, the catalyst is filtered off. The filtrateis evaporated under reduced pressure to give the title compound as anoil. The free base thus obtained is converted to the oxalate 3/2 hydrateof the title compound in a usual manner, m.p. 163°-166° C.(recrystallzed from ethanol-diethyl ether).

EXAMPLE 31 Preparation ofN-(hexahydro-1H-1,4-diazepin-6-yl)-1H-indazole-3-carboxamide

The 5/4 oxalate 1/2 hydrate of title compound is prepared insubstantially the same manner as in Example 30, usingN-(1,4-dibenzylhexahydro-1H-1,4-diazepin-6-yl)-1H-indazole-3-carboxamidein place ofN-(1-benzyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-1H-indazole-3-carboxamidein Example 30, m.p. 219°-222° C. (recrystallized from ethanol-diethylether).

EXAMPLE 32 Preparation ofN-(1-benzyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-1H-indazole-3-carboxamide:

To a solution of 6-amino-1-benzyl-4-methylhexahydro-1H-1,4-diazepine(1.0 g) in dichloromethane (20 ml), 1H-indazole-3-carboxylic acid (740mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (877mg) are added, and the resulting mixture is stirred at 25° C. for 2hours. The reaction mixture is washed successively with water and 10%aqueous sodium hydroxide solution, and dried over magnesium sulfate. Thesolvent is evaporated under reduced pressure, and the residue ischromatographed on silica gel with elution of acetone. Fractionscontaining the title compound are pooled and evaporated under reducedpressure to give the title compound (0.9 g) as an oil. The free basethus obtained is converted to the hemifumarate of the title compound ina usual manner, m.p. 192°-194° C. (recrystallized from ethanol).

¹ H-NMR spectrum (DMSO-D₆, δppm): 2.40 (3H, s, --NCH₃), 2.3-3.0 (8H, m),3.70 (2H, s, --NCH₂ Ph), 4.0-4.4 (1H, m, --CONHCH--), 7.1-7.5 (8H, m,5-H, 6-H, 7-H, --CH₂ C₆ H₅), 8.16 (each 1H, each d, each J=9Hz, 4-H,--CONH--), 13.5 (1H, br s, --NH).

EXAMPLE 33 Preparation ofN-(1-benzyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-1-methyl-1H-indazole-3-carboxamide

Oxalate 1/4 ethanol 3/2 hydrate of the title compound is prepared insubstantially the manner as in Example 32, using1-methyl-1H-indazole-3-carboxylic acid in place of1H-indazole-3-carboxylic acid in Example 32, m.p. 80°-85° C.(recrystallized from ethanol-diethyl ether).

¹ H-NMR spectrum (DMSO-D₆, δppm): 2.30 (3H, s, --NCH₃), 2.1-3.5 (8H, m),3.75 (2H, s, --NCH₂ Ph), 4.16 (3H, s, --NCH₃), 4.2-4.7 (1H, m,--CONHCH--), 7.1-7.6 (7H, m), 7.76 (1H, d, J=8Hz, 7-H), 8.16 (1H, d,J=8Hz, 4-H), 8.92 (1H, d, J=9Hz, --CONH--).

EXAMPLE 34 Preparation ofN-(1,4-dimethylhexahydro-1H-1,4-diazepin-6-yl)-1-methyl-1H-indazole-3-carboxamide

3/2 Fumarate of the title compound is prepared in substantially the samemanner as in Example 1, using 1-methyl-1H-indazole-3-carboxylic acid and6-acetylamino-1,4-dimethylhexahydro-1H-1,4-diazepine in place of1H-indazole-3-carboxylic acid and6-acetylamino-1-(3-methylbenzyl)-4-methylhexahydro-1H-1,4-diazepine inExample 1, m.p. 176°-180° C. (recrystallized from ethanol).

EXAMPLE 35 Preparation ofN-(1-benzyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-1-ethyl-1H-indazole-3-carboxamide

A mixture of 1-ethyl-1H-indazole-3-carboxylic acid (8.6 g), thionylchloride (8 ml) and chloroform (80 ml) is refluxed for 1 hour. Afterremoval of solvent, the residue is dissolved in dichloromethane (100ml), and a solution of6-amino-1-benzyl-4-methylhexahydro-1H1,4-diazepine (9.9 g) andtriethylamine (9.2 g) in dichloromethane (100 ml) is added dropwise tothe mixture at 0° C. The reaction mixture is stirred at 25° C. for 2hours, washed with water, and dried over sodium sulfate. The solvent isevaporated under reduced pressure, and the residue is chromatographed onsilica gel with elution of acetone. Fractions containing the titlecompound are pooled and evaporated under reduced pressure to give thetitle compound (13.6 g) as an oil.

(a) The free base thus obtained is converted to the fumarate of thetitle compound in a usual manner, m.p. 135°-137° C. (recrystallized fromethanol).

¹ H-NMR spectrum (DMSO-D₆, δppm): 1.48 (3H, t, J=7Hz, --CH₂ CH₃), 2.44(3H, s, --NCH₃), 2.6-3.2 (8H, m), 3.66 (2H, s, --NCH₂ Ph), 4.0-4.5 (1H,m, --CONHCH--), 4.54 (2H, q, J=7Hz, --CH₂ CH₃), 7.1-7.6 (7H, m), 7.76(1H, d, J=8Hz, 7-H), 8.14 (each 1H, each d, each J=9Hz, 4-H, --CONH--).

(b) The free base obtained above is converted to the 3/2 oxalate 3/4hydrate of the title compound in a usual manner, m.p. 77°-81° C.(recrystallized from ethanol-diethyl ether).

EXAMPLE 36 Preparation ofN-(1-methylhexahydro-1H-1,4-diazepin-6-yl)-1-ethyl-1H-indazole-3-carboxamide

3/2 Oxalate 3/4 hydrate of the title compound is prepared insubstantially the same manner as in Example 30, usingN-(1-benzyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-1-ethyl-1H-indazole-3-carboxamidein place ofN-(1-benzyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-1H-indazole-3-carboxamidein Example 30, m.p. 107°-111° C. (recrystallized from ethanol-diethylether).

¹ H-NMR spectrum (DMSO-D₆, δppm): 1.46 (3H, t, J=7Hz, --CH₂ CH₃), 2.48(3H, s, --NCH₃), 2.7-3.5 (8H, m), 4.54 (3H, q, J=7Hz, --CH₂ CH₃,--CONHCH--), 7.1-7.6 (2H, m, 5-H, 6-H), 7.78 (1H, d, J=8Hz, 7-H), 8.16(1H, d, J=8Hz, 4-H), 8.38 (1H, d, J=9Hz, --CONH--).

EXAMPLE 37 Preparation ofN-[1-(3-methylbenzyl)-4-methylhexahydro-1H-1,4-diazepin-6-yl]-1-ethyl-1H-indazole-3-carboxamide

A mixture ofN-(1-methylhexahydro-1H-1,4-diazepin-6-yl)-1-ethyl-1H-indazole-3-carboxamide(1.8 g), potassium carbonate (4.1 g), sodium iodide (0.9 g),3-methylbenzyl chloride (0.85 g) and methyl ethyl ketone (100 ml) isrefluxed with stirring for 6 hours. After cooling, the reaction mixtureis filtered, and the filtrate is concentrated under reduced pressure.The residue is chromatographed on silica gel with elution ofchloroform-methanol (20:1). Fractions containing the title compound arepooled and evaporated under reduced pressure to give the title compound(1.9 g) as an oil. The free base thus obtained is converted to thefumarate of the title compound in a usual manner, m.p. 135°-137° C.(recrystallized from ethanol-diethyl ether).

¹ H-NMR spectrum (DMSO-D₆, δppm): 1.48 (3H, t, J=7Hz, --CH₂ CH₃), 2.20(3H, s, --CH₂ C₆ H₄ CH₃), 2.43 (3H, s, --NCH₃), 2.6-3.1 (8H, m), 3.64(2H s, --CH₂ C₆ H₄ CH₃), 4.0-4.5 (1H, m, --CONHCH--), 4.55 (2H, q,J=7Hz, --CH₂ CH₃), 6.8-7.6 (7H, m), 7.75 (1H, d, J=8Hz, 7-H), 8.13 (each1H, each d, each J=9Hz, 4-H, --CONH--).

EXAMPLE 38-42

Various compounds listed in the following Table 4 are prepared insubstantially the same manner as in Example 37, usingN-(1-methylhexahydro-1H-1,4-diazepin-6-yl)-1-ethyl-1H-indazole-3-carboxamideand the appropriate arylalkylating, heteroarylalkylating or alkylatingagents.

                  TABLE 4                                                         ______________________________________                                         ##STR46##                                                                                                           Recry.                                 Ex.  R.sub.2        Q         m.p. (°C.)                                                                      solv.                                  ______________________________________                                        38                                                                                  ##STR47##     fumarate  127˜129                                                                          A                                      39                                                                                  ##STR48##     difumarate. 1/4H.sub.2 O                                                                122˜127                                                                          A                                      40                                                                                  ##STR49##     dioxalate 94˜97                                                                            A-E                                    41                                                                                  ##STR50##     sesqui- oxalate. 1/2H.sub.2 O                                                           103˜106                                                                          A-E                                    42                                                                                  ##STR51##     sesqui- oxalate                                                                         73˜79                                                                            A-E                                    ______________________________________                                    

EXAMPLE 43 Preparation ofN-(1-benzoyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-1-ethyl-1H-indazole-3-carboxamide

To a solution ofN-(4-methylhexahydro-1H-1,4-diazepin-6-yl)-1-ethyl-1H-indazole-3-carboxamide(1.0 g) in dichloromethane (20 ml), benzoic anhydride (1.5 g) is added,and the mixture is stirred at 25° C. for 16 hours. The reaction mixtureis washed with saturated sodium bicarbonate, and dried over sodiumsulfate. The solvent is evaporated under reduced pressure, and theresidue is chromatographed on silica gel with elution of acetone.Fractions containing the title compound are pooled and evaporated underreduced pressure to give the title compound (1.3 g) as an oil. The freebase thus obtained is converted to the oxalate 3/4 hydrate of the titlecompound in a usual manner, m.p. 100°-103° C. (recrystallized fromethanol-diethyl ether).

¹ H-NMR spectrum (DMSO-D₆, δppm): 1.45 (3H, t, J=8Hz, --CH₂ CH₃), 2.72(3H, s, --NCH₃), 2.6-4.2 (8H, m), 4.52 (2H, q, J=8Hz, --CH₂ CH₃), 7.52(5H, s, --COC₆ H₅) 7.1-7.6 (2H, m, 5-H, 6-H), 7.76 (1H, d, J=8Hz, 7-H),8.12 (1H, d, J=8Hz, 4-H), 8.47 (1H, d, J=8Hz, --CONH--).

EXAMPLE 44-51

Various compounds listed in the following Table 5 are prepared insubstantially the same manner as in Example 32, using6-amino-1-benzyl-4-methylhexahydro-1H-1,4-diazepine and thecorresponding 1H-indazole-3-carboxylic acid derivatives.

                  TABLE 5                                                         ______________________________________                                         ##STR52##                                                                                                           Recry.                                 Ex.  R.sub.4        Q          m.p. (°C.)                                                                     solv.                                  ______________________________________                                        44   CH.sub.2 CH.sub.2 CH.sub.3                                                                   sesqui-    70˜76                                                                           A-E                                                        oxalate.                                                                      1/2H.sub.2 O                                              45                                                                                  ##STR53##     sesqui- oxalate. 3/4H.sub.2 O                                                            77˜80                                                                           A-E                                    46   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                          sesqui-    69˜74                                                                           A-E                                                        oxalate.                                                                      1/2H.sub.2 O                                              47                                                                                  ##STR54##     5/4oxalate. 5/4H.sub.2 O                                                                 72˜75                                                                           A-E                                    48   CH.sub.2 CHCH.sub.2                                                                          sesqui-    73˜77                                                                           A-E                                                        oxalate.                                                                      1/2H.sub.2 O                                              49                                                                                  ##STR55##     sesqui-  oxalate. 1/2H.sub.2 O                                                           82˜85                                                                           A-E                                    50                                                                                  ##STR56##     sesqui- oxalate. 1/4H.sub.2 O                                                            86˜90                                                                           A-E                                    51                                                                                  ##STR57##     sesqui- oxalate. 1/4H.sub.2 O                                                            76˜79                                                                           A-E                                    ______________________________________                                    

EXAMPLE 52 Preparation ofN-(1-benzyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-1-acetyl-1H-indazole-3-carboxamide

To a solution ofN-(1-benzyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-1H-indazole-3-carboxamide(1.0 g) in dichloromethane (10 ml), acetic anhydride (0.56 g) is added;and the mixture is stirred at 25° C. for 16 hours. The reaction mixtureis washed with saturated sodium bicarbonate and dried over sodiumsulfate. The solvent is evaporated under reduced pressure, and theresidue is chromatographed on silica gel with elution of acetone.Fractions containing the title compound are pooled and evaporated underreduced pressure to give the title compound (0.92 g) as an oil. The freebase thus obtained is converted to the fumarate 1/4 hydrate of the titlecompound in a usual manner, m.p. 166°-168° C. (recrystallized fromethanol).

EXAMPLE 53 Preparation ofN-(1-benzyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-1-propionyl-1H-indazole-3-carboxamide

Fumarate of the title compound is prepared in substantially the samemanner as in Example 52, using propionic anhydride in place of aceticanhydride in Example 52, m.p. 185°-187° C. (recrystallized fromethanol).

¹ H-NMR spectrum (DMSO-D₆, δppm): 1.25 (3H, t, J=7Hz, --COCH₂ CH₃), 2.45(3H, s, --NCH₃), 2.6-3.1 (8H, m), 3.31 (2H, q, J=7Hz, --COCH₂ CH₃), 3.69(2H, s, --CH₂ Ph), 4.1-4.5 (1H, m, --CONHCH--), 7.1-7.8 (7H, m, 5-H,6-H, --CH₂ C₆ H₅), 8.1-8.6 (3H, m, 4-H, 7-H, --CONH--).

EXAMPLE 54 Preparation ofN-(1-benzyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-1-benzoyl-1H-indazole-3-carboxamide

Fumarate 1/2 hydrate of the title compound is prepared in substantiallythe same manner as in Example 52, using benzoic anhydride in place ofacetic anhydride in Example 52, m.p. 187°-189° C. (recrystallized fromethanol).

¹ H-NMR spectrum (DMSO-D₆, δppm): 2.40 (3H, s, --NCH₃), 2.6-3.2 (8H, m),3.60 (2H, s, --CH₂ Ph), 3.9-4.4 (1H, m, --CONHCH--), 7.12 (4H, m),7.4-7.9 (4H, m), 7.9-8.6 (5H, m).

EXAMPLE 55 Preparation ofN-(1-benzyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-1-methoxycarbonyl-1H-indazole-3-carboxamide

To a solution ofN-(1-benzyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-1H-indazole-3-carboxamide(0.92 g) and triethylamine (0.77 g) in dichloromethane (30 ml), methylchloroformate (0.48 g) is added dropwise at 0° C., and the mixture isstirred at 25° C. for 16 hours. The reaction mixture is washed withsaturated sodium bicarbonate and dried over sodium sulfate. The solventis evaporated under reduced pressure, and the residue is chromatographedon silica gel with elution of acetone. Fractions containing the titlecompound are pooled and evaporated under reduced pressure to give thetitle compound (0.7 g) as an oil. The free base thus obtained isconverted to the fumarate of the title compound in a usual manner, m.p.158°-160° C. (recrystallized from ethanol).

¹ H-NMR spectrum (DMSO-D₆, δppm): 2.40 (3H, s, --NCH₃), 2.6-3.1 (8H, m),3.66 (2H, s, --CH₂ Ph), 4.13 (3H, s, --COOCH₃), 4.0-4.4 (1H, m,--CONHCH--), 7.1-7.9 (7H, m), 8.1-8,5 (3H, m).

EXAMPLE 56 Preparation ofN-(1-benzyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-1-(2-butanon-3-yl)-1H-indazole-3-carboxamide

To a solution ofN-(1-benzyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-1-1H-indazole-3-carboxamide(1.0 g) in tetrahydrofuran (20 ml), potassium tert-butoxide (0.32 g) isadded at 0° C., and the mixture is stirred at the same temperature for30 minutes. 3-Chloro-2-butanone (0.29 g) is added to the mixture at 0°C. and stirred at 25° C. for 16 hours. The reaction mixture is washedwith water and dried over sodium sulfate. The solvent is evaporatedunder reduced pressure, and the residue is chromatographed on silica gelwith elution of acetone. Fractions containing the title compound arepooled and evaporated under reduced pressure to give the title compound(0.54 g) as an oil. The free base thus obtained is converted to the 3/2oxalate 1/4 hydrate of the title compound in a usual manner, m.p.97°-100° C. (recrystallized from ethanol-diethyl ether).

¹ H-NMR spectrum (DMSO-D₆, δppm): 1.76 (3H, d, J=7Hz, --CHCH₃), 2.02(3H, s, --COCH₃), 2.80 (3H, s, --NCH₃), 2.6-3.5 (8H, m), 3.75 (2H, s,--CH₂ Ph), 4.46 (1H, m, --CONHCH--), 5.77 (1H, q, J=7Hz, --CHCH₃),7.1-7.6 (7H, m, 5-H, 6-H, --CH₂ C₆ H₅), 7.74 (1H, d, J=8Hz, 7-H), 8.16(1H, J=8Hz, 4-H), 8.40 (1H, d, J=8Hz, --CONH--).

EXAMPLE 57 Preparation ofN-(1-benzyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-1-(2-hydroxyethyl)-1H-indazole-3carboxamide

Oxalate 1/2 hydrate of the title compound is prepared in substantiallythe same manner as in Example 56, using 2-chloroethanol in place of3-chloro-2-butanone in Example 56, m.p. 84°-89° C. (recrystallized fromethanol-diethyl ether).

¹ H-NMR spectrum (DMSO-D₆, δppm): 2.81 (3H, s, --NCH₃), 2.6-3.5 (8H, m),3.76 (2H, s, --CH₂ Ph), 3.90 (2H, t, J=6Hz, --CH₂ CH₂ OH), 4.54 (2H, t,J=6Hz, --CH₂ CH₂ OH), 6.9-7.9 (7H, m), 7.75 (1H, d, J=8Hz, 7-H), 8.14(1H, d, J=8Hz, 4-H), 8.41 (1H, d, J=8Hz, --CONH--).

EXAMPLE 58-65

Various compounds listed in the following Table 6 are prepared insubstantially the same manner as in Example 32, using6-amino-1-benzyl-4-methylhexahydro-1H-1,4-diazepine and thecorresponding substituted 1H-indazole-3-carboxylic acids.

                  TABLE 6                                                         ______________________________________                                         ##STR58##                                                                                                           Recry.                                 Ex.  (R.sub.5).sub.p                                                                       Q                m.p. (°C.)                                                                      solv.                                  ______________________________________                                        58   5-F     dioxalate.1/4EtOH.1/4H.sub.2 O                                                                 118˜121                                                                          A-AC                                   59   4-Cl    dioxalate.EtOH   108˜111                                                                          A-AC                                   60   5-Cl    sesquioxalate.1/4EtOH.1/2H.sub.2 O                                                             142˜146                                                                          A-AC                                   61   6-Cl    dioxalate.1/4H.sub.2 O                                                                         119˜124                                                                          A-AC                                   62   7-Cl    dioxalate.1/2H.sub.2 O                                                                         145˜148                                                                          A-AC                                   63   5-Me    dioxalate.3/4H.sub.2 O                                                                         112˜115                                                                          A-AC                                   64   6-F     dioxalate        126˜130                                                                          A-AC                                   65   5-F     dioxalate.1/2EtOH.3/4H.sub.2 O                                                                 120˜123                                                                          A-AC                                   ______________________________________                                    

EXAMPLE 66 Preparation ofN-(1-benzyl-3,4-dimethylhexahydro-1H-1,4-diazepin-6-yl)-1H-indazole-3-carboxamide

To a solution of 1H-indazole-3-carboxylic acid (2.2 g) inN,N-dimethylformamide (40 ml), N,N'-carbonyldiimidazole (2.2 g) isadded, and the mixture is heated at 60° C. for 3.5 hours. A solution of6-amino-1-benzyl-3,4-dimethylhexahydro-1H-1,4-diazepine (3.0 g) inN,N-dimethylformamide (10 ml) is added to the mixture, and the mixtureis stirred at 25° C. for 2 hours. The solvent is evaporated underreduced pressure, and the residue is diluted with water and extractedwith chloroform. The organic layer is washed successively with 10%aqueous sodium hydroxide solution, water and saturated aqueous sodiumchloride solution, and dried over sodium sulfate. The solvent isevaporated under reduced pressure, and the residue is chromatographed onsilica gel with elution 10% methanol-acetone. Fractions containing thetitle compound are pooled and evaporated under reduced pressure to givethe title compound (0.9 g) which is one isomer with lower polarity intwo isomers produced in the above reaction, m.p. 203°-205° C.(recrystallized from isopropyl alcohol).

EXAMPLE 67 Preparation ofN-(1-benzyl-3,4-dimethylhexahydro-1H-1,4-diazepin-6-yl)-1H-indazole-3-carboxamide

The title compound (1.9 g) is obtained by the same silica gel columnchromatography in Example 66 as the other isomer with higher polarity intwo isomers produced in the reaction of Example 66, m.p. 162°-163° C.(recrystallized from ethanol).

EXAMPLE 68 Preparation ofN-(1-benzyl-2,4-dimethylhexahydro-1H-1,4-diazepin-6-yl)-1H-indazole-3-carboxamide

1/4 Hydrate of the title compound which is one isomer with lowerpolarity is prepared in substantially the same manner as in Example 66,using 6-amino-1-benzyl-2,4-dimethylhexahydro-1H-1,4-diazepine in placeof 6-amino-1-benzyl-3,4-dimethylhexahydro-1H-1,4-diazepine in Example66, m.p. 199°-202° C. (recrystallized from isopropyl alcohol).

EXAMPLE 69 Preparation ofN-(1-benzyl-2,4-dimethylhexahydro-1H-1,4-diazepin-6-yl)-1H-indazole-3-carboxamide

The title compound is obtained by the same silica gel columnchromatography in Example 68 as the other isomer with higher polarity,m.p. 164°-165° C. (recrystallized from toluene).

EXAMPLE 70 Preparation of (1,4-dimethylhexahydro-1H-1,4-diazepin-6-yl)1H-indazole-3-carboxylate

To a solution of 1,4-dimethy-6-hydroxyhexahydro-1H-1,4-diazepine (1.9 g)in anhydrous tetrahydrofuran (10 ml), a solution of n-butyllithium inhexane (9.4 g) is added dropwise under nitrogen stream at 25° C., andthe mixture is stirred for 30 minutes at the same temperature. To thereaction mixture is added dropwise, the reaction mixture prepared by thefollowing method; to a solution of 1H-indazole-3-carboxylic acid (2.0 g)in anhydrous N,N-dimethylformamide (20 ml), N,N'-carbonyldiimidazole(2.0 g) is added at 25° C., and the mixture is heated at 80° C. for 4.5hours and cooled to 25° C. The resulting reaction mixture is refluxedwith stirring for 1 hour. Tetrahydrofuran is evaporated under reducedpressure, and the residue is diluted with water, extracted with diethylether. The organic layer is washed with saturated sodium chloridesolution and dried over magnesium sulfate. The solvent is evaporatedunder reduced pressure, and the residue is chromatographed on silica gelwith elution of chloroform-methanol ( 9:1). Fractions containing thetitle compound are pooled and evaporated under reduced pressure to givethe title compound (2.4 g) as an oil. The free base is converted to 5/2fumarate 1/4 ethanol of the title compound in a usual manner, m.p.184°-185° C. (recrystallized from ethanol).

EXAMPLE 71

A solution of Diindazole[2,3-a,2',3'-d]pirazine-7,14-dione (25 g) and6-amino-4-(3-methylbenzyl)-1-methylhexahydro-1,4-diazepine (40.5 g) inN,N -dimethylformamide (250 ml) is heated at 60°-80° C. for 5 hours. Thesolvent is evaporated under reduced pressure, and the residue isdissolved in chloroform. The solution is washed with water and saturatedsodium chloride solution, and dried over magnesium sulfate. The solventis evaporated under reduced pressure. The oil thus obtained is purifiedby silica gel chromatography in the same manner as in Example 1 to givethe title compound in Example 1.

EXAMPLE 72 Preparation of6-acetylamino-1-benzyl-4-methylhexahydro-1H-1,4-diazepine

To a solution of 2-chloromethyl-1-benzyl-4-methylpiperazine (6.1 g)prepared according to the method of Helv. Chim. Acta, 45, 2383-2402(1962) in acetonitrile (60 ml), sodium azide (3.3 g) is added, and themixture is refluxed for 2 hours. The reaction mixture is filtered, andthe filtrate is concentrated under reduced pressure. The residue isdissolved in toluene (100 ml), and a solution of 70% sodiumbis(2-methoxyethoxy) aluminum hydride in toluene (10.4 g) is added insmall portions to the above solution at 0° C. The resulting mixture isstirred at 25° C. for 3 hours, and then poured into ice-water, and 48%aqueous sodium hydroxide solution is added to the resulting solution.The aqueous layer is extracted with toluene, and the combined organiclayer is dried over sodium sulfate. The solvent is evaporated underreduced pressure. The residue is dissolved in chloroform (200 ml), andacetic anhydride (5.2 g) is added to the solution. The mixture isstirred at 25° C. for 2 hours, washed successively with 48% aqueoussodium hydroxide solution and water, and dried over magnesium sulfate.The solvent is evaporated under reduced pressure, and the residue ischromatographed on silica gel with elution of chloroform-methanol(20:1). Fractions containing the title compound are pooled andevaporated under reduced pressure to give the title compound (1.0 g) asan oil.

¹ H-NMR spectrum (CDCl₃, δppm): 1.85 (3H, s, --COCH₃), 2.35 (3H, s,--NCH₃), 3.46, 3.72 (each 1H, each d, each J=13Hz, --CH₂ Ph), 3.98 (1H,m, --CONHCH--), 6.35 (1H, d, --CONH--), 7.30 (5H, m, --CH₂ C₆ H₅).

EXAMPLE 73 Preparation of6-acetylamino-1,4-dimethylhexahydro-1H-1,4-diazepine

The title compound as an oil is prepared in substantially the samemanner as in Example 72, using 2-chloromethyl-1,4-dimethylpiperazine inplace of 2-chloromethyl-1-benzyl-4-methylpiperazine in Example 72.

¹ H-NMR spectrum (CDCl₃, δppm): 2.02 (3H, s, --COCH₃), 2.37 [(6H, s,2(--NCH₃)], 2.32-2.52 (2H, m), 2.56-2.66, 2.72-2.83 (6H, m), 4.04-4.12(1H, m, --CONHCH--).

EXAMPLE 74 Preparation of6-acetylamino-1-methylhexahydro-1H-1,4-diazepine

6-Acetylamino-1-benzyl-4-methylhexahydro-1H-1,4-diazepine (20 g) isdissolved in ethanol (400 ml) and acetic acid (70 ml), and hydrogenatedover 10% palladium on carbon (2 g) at about 50° C. After the calculatedamount of the hydrogen is absorbed, the catalyst is filtered off. Thefiltrate is evaporated under reduced pressure to give acetate of thetitle compound (30 g) as an oil.

EXAMPLE 75 Preparation of6-acetylamino-1,4-diethylhexahydro-1H-1,4-diazepine

The title compound as an oil is prepared in substantially the samemanner as in Example 72, using 2-chloromethyl-1,4-diethylpiperazine inplace of 2-chloromethyl-1-benzyl-4-methylpiperazine in Example 72.

EXAMPLE 76 Preparation of6-acetylamino-1,4-dibenzylhexahydro-1H-1,4-diazepine

The title compound as an oil is prepared in substantially the samemanner as in Example 72, using 2-chloromethyl-1,4-dibenzylpiperazine inplace of 2-chloromethyl-1-benzyl-4-methylpiperazine in Example 72.

EXAMPLE 77 Preparation of6-acetylamino-1-(3-methylbenzyl)-4-methylhexahydro-1H-1,4-diazepine

A mixture of acetate of 6-acetylamino-1-methylhexahydro-1H-1,4-diazepine(3.0 g), 3-methylbenzyl chloride (3.5 g), potassium carbonate (17 g),sodium iodide (0.1 g) and methyl ethyl ketone (200 ml) is refluxed withstirring for 16 hours. The reaction mixture is filtered, and thefiltrate is concentrated under reduced pressure. The residue ischromatographed on silica gel with elution of chloroform-methanol(20:1). Fractions containing the title compound are pooled andevaporated under reduced pressure to give the title compound as an oil.

¹ H-NMR spectrum (CDCl₃, δppm): 1.86 (3H, s, --COCH₃), 2.34 (3H, s,--CH₂ C₆ H₄ CH₃), 2.36 (3H, s, --NCH₃), 3.43, 3.67 (each 1H, each d,J=12Hz, --CH₂ C₆ H₄ CH₃), 3.97 (1H, m, --CONHCH--), 6.45 (1H, d,--CONH--), 7.0-7.4 (4H, m, --CH₂ C₆ H₄ CH₃).

EXAMPLE 78-104

Various compounds listed in Table 7 are prepared in substantially thesame manner as in Example 77, using the appropriate alkylating,arylalkylating, or heteroaryl-alkylating agents in place of3-methylbenzyl chloride in Example 77.

                  TABLE 7                                                         ______________________________________                                         ##STR59##                                                                    Ex.       R.sub.2                                                             ______________________________________                                        78                                                                                       ##STR60##                                                          79                                                                                       ##STR61##                                                          80                                                                                       ##STR62##                                                          81                                                                                       ##STR63##                                                          82                                                                                       ##STR64##                                                          83                                                                                       ##STR65##                                                          84                                                                                       ##STR66##                                                          85                                                                                       ##STR67##                                                          86                                                                                       ##STR68##                                                          87                                                                                       ##STR69##                                                          88                                                                                       ##STR70##                                                          89                                                                                       ##STR71##                                                          90                                                                                       ##STR72##                                                          91                                                                                       ##STR73##                                                          92        CH.sub.2 CHCH.sub.2                                                 93                                                                                       ##STR74##                                                          94                                                                                       ##STR75##                                                          95                                                                                       ##STR76##                                                          96                                                                                       ##STR77##                                                          97                                                                                       ##STR78##                                                          98                                                                                       ##STR79##                                                          99        CH.sub.2 CH.sub.3                                                   100                                                                                      ##STR80##                                                          101                                                                                      ##STR81##                                                          102                                                                                      ##STR82##                                                          103                                                                                      ##STR83##                                                          104                                                                                      ##STR84##                                                          ______________________________________                                    

EXAMPLE 105 Preparation of1,4-dimethyl-6-hydroxyhexahydro-1H-1,4-diazepine

A solution of 6-acetoxyhexahydro-1H-1,4-diazepine dihydrobromide (20 g)prepared according to the method of J. Org. Chem., 36, 1711 (1971), 35%formaldehyde (16.1 g) and formic acid (20 ml) is refluxed with stirringfor 7 hours. The solvent is evaporated under reduced pressure, and theresidue is diluted with cool water. The excess potassium carbonate isadded to the aqueous solution, and the resulting solution is extractedwith chloroform. The organic layer is dried over magnesium sulfate, andthe solvent is evaporated under reduced pressure to give the titlecompound (11.5 g) as a pale yellow oil.

¹ H-NMR spectrum (CDCl₃, δppm): 2.41 [(6H, s, 2(--NCH₃)], 2.38-2.50 (2H,m), 2.66-2.84 (6H, m), 3.77 (1H, m, --CONHCH--).

EXAMPLE 106

(1) To a mixture of tris(hydroxymethyl)nitromethane (118.9 g), sodiumbicarbonate (40 g) and water (1000 ml),N-benzyl-N'-methylethylenediamine (123 g) is added, and the reactionmixture is heated at about 50° C. for 2 hours. After cooling, thesolution is extracted with dichloromethane, and the organic layer iswashed with saturated aqueous sodium chloride and dried over magnesiumsulfate. The solvent is evaporated under reduced pressure to give1-benzyl-6-hydroxymethyl-4-methyl-6-nitrohexahydro-1H-1,4-diazepine asan oil.

¹ H-NMR spectrum (CDCl₃, δppm): 2.41 [(6H, s, 2(--NCH₃)], 2.47-2.80 (4H,m), 2.91-3.51 (4H, m), 3.63, 3.73 (each 1H, each d, each J=12Hz,--CH_(2Ph)), 3.80 (2H, s, --CH₂ OH).

(2) To a solution of1-benzyl-6-hydroxymethyl-4-methyl-6-nitrohexahydro-1H-1,4-diazepine inmethanol (800 ml), potassium tert-butoxide (97 g) is added, and thesolution is heated at about 40° C. for 30 minutes. The solvent isevaporated under reduced pressure, and the residue is diluted in asolution of hydroxylamine hydrochloride (60 g) in water (500 ml) andextracted with dichloromethane. The organic layer is washed withsaturated aqueous sodium chloride solution and dried over magnesiumsulfate. The solvent is evaporated under reduced pressure, and theresidue is chromatographed on silica gel with elution of ethyl acetate.Fractions containing the object compound are pooled and evaporated underreduced pressure to give1-benzyl-4-methyl-6-nitrohexahydro-1H-1,4-diazepine (45 g) as a paleyellow oil.

¹ H-NMR spectrum (CDCl₃, δppm): 2.44 (3H, s, --NCH₃), 2.50-2.78 (4H, m),3.10-3.45 (4H, m), 3.74 (2H, dd, J=15Hz, J=20Hz, --CH₂ Ph), 4.62 (1H,quint, --CONHCH--)

(3) 1-Benzyl-4-methyl-6-nitrohexahydro-1H-1,4-diazepine (38 g) isdissolved in 95% ethanol (700 ml) and hydrogenated over Raney-nickel(about 5 g) at 25° C. After the calculated amount of the hydrogen isabsorbed, the catalyst is filtered off. The filtrate is evaporated underreduced pressure to give a crude oil. The oil is dissolved in chloroform(200 ml), and acetic anhydride (30 g) is added to the solution. Thereaction mixture is stirred at 25° C. for 2 hours, and water is added tothe reaction mixture. The aqueous layer is separated and basified withsodium hydroxide solution, and extracted with chloroform. The organiclayer is washed successively with water and saturated aqueous sodiumchloride solution, and dried over magnesium sulfate The solvent isevaporated under reduced pressure, and the residue is chromatographed onsilica gel with elution of chloroform-methanol (9:1). Fractionscontaining the object compound are pooled and evaporated under reducedpressure to give the title compound (49 g) in Example 72.

EXAMPLE 107

6-Acetylamino-1-benzyl-4-methylhexahydro-1H-1,4-diazepine (19.0 g) isdissolved in ethanol (300 ml) and acetic acid (30 ml) and hydrogenatedover 10% palladium on carbon (3 g) at 25° C. After the calculated amountof the hydrogen is absorbed, the catalyst is filtered off. The filtrateis evaporated under reduced pressure to give an oil. 35% Formaldehyde(19.0 g) and formic acid (25 ml) is added to the oil, and the reactionmixture is refluxed with stirring for 7 hours. The solvent is evaporatedunder reduced pressure, and the residue is diluted with aqueous sodiumhydroxide solution. Excess potassium carbonate is added to the solution,and the solution is extracted with chloroform. The organic solvent isdried over magnesium sulfate, and the solvent is evaporated underreduced pressure. The residue is chromatographed on silica gel withelution of chloroform-methanol (9:1). Fractions containing the objectcompound are pooled and evaporated under reduced pressure to give thetitle compound in Example 73.

EXAMPLE 108 Preparation of6-amino-1-benzyl-2,4-dimethylhexahydro-1H-1,4-diazepine

(1) To a solution of 2-benzylamino-1-propanol (113.9 g) in chloroform(700 ml), thionyl chloride (140 ml) is added dropwise at 0° C., and themixture is refluxed for 8.5 hours. The solvent is evaporated underreduced pressure, and isopropyl alcohol (200 ml) is added in smallportions to the residue at 0° C. The resulting precipitates arecollected and washed successively with isopropyl alcohol and diethylether, and dried to give N-(β-chloropropyl)benzylamine hydrochloride(139.8 g).

(2) N-(β-Chloropropyl)benzylamine hydrochloride (50.0 g) is added insmall portion to 30% monomethylamine ethanol solution (250 ml) at 0° C.,and the reaction mixture is stirred at 50° C. for 20 hours. The solventis evaporated under reduced pressure, and the residue is diluted in asolution of potassium hydroxide (34 g) in water (53 ml) and extractedwith chloroform. The organic solvent is dried over magnesium sulfate andevaporated under reduced pressure to give an oil. N² -Benzyl-N¹-methyl-1,2-propylenediamine (29.8 g) is obtained from the oil by vacuumdistillation, b.p. 96°-97° C. (0.04 mmHg).

(3) To a solution of tris(hydroxymethyl)nitromethane (10.3 g), sodiumbicarbonate (3 g), and water (100 ml), N² -benzyl-N¹-methyl-1,2-propylenediamine (12 g) is added, and the reaction mixtureis heated at about 50° C. for 2.5 hours. After cooling, the reactionmixture is extracted with dichloromethane, and the organic layer iswashed with water and saturated aqueous sodium chloride and dried overmagnesium sulfate. The solvent is evaporated under reduced pressure togive an oil. Potassium tert-butoxide (7.6 g) is added in small portionsto the solution of the above oil in methanol (100 ml), and the solutionis heated at about 30° C. for 30 minutes. The solvent is evaporatedunder reduced pressure, and the residue is diluted in a solution of 95%hydroxylamine hydrochloride (5.0 g) in water (50 ml) and extracted withdichloromethane. The organic layer is washed with saturated aqueoussodium chloride and dried over magnesium sulfate. The solvent isevaporated under reduced pressure, and the residue is chromatographed onsilica gel with elution of ethyl acetate. Fractions containing theobject compound are pooled and evaporated under reduced pressure to give1-benzyl-2,4-dimethyl-6-nitrohexahydro-1H-1,4-diazepine (5.1 g) as apale yellow oil.

(4) 1-Benzyl-2,4-dimethyl-6-nitrohexahydro-1H-1,4-diazepine (5.1 g) isdissolved in ethanol (100 ml) and acetic acid (5 ml) and hydrogenatedover Raney-nickel (about 1 g) at 25° C. After the calculated amount ofthe hydrogen is absorbed, the catalyst is filtered off. The filtrate isevaporated under reduced pressure. The residue is dissolved inchloroform (100 ml), and acetic anhydride (4.0 g) is added to thesolution. The reaction mixture is stirred for 2 hours at 25° C., dilutedwith aqueous sodium hydroxide solution, and extracted with chloroform.The organic layer is washed successively with water, aqueous sodiumhydroxide solution, and saturated aqueous sodium chloride solution, anddried over magnesium sulfate. The solvent is evaporated under reducedpressure, the residue is chromatographed on silica gel with elution ofchloroform-methanol (9:1). Fractions containing the object compound arepooled and evaporated under reduced pressure to give6-acetylamino-1-benzyl-2,4-dimethylhexahydro-1H-1,4-diazepine (1.8 g) asan oil. The above compound is dissolved in 10% hydrochloric acid (20 ml)and is refluxed for 2 hours. After cooling, the reaction mixture isbasified with aqueous sodium hydroxide solution and extracted withchloroform. The organic layer is washed successively with water andsaturated aqueous sodium chloride solution, and dried over magnesiumsulfate. The solvent is evaporated under reduced pressure to give thetitle compound (1.5 g).

EXAMPLE 109 Preparation of6-amino-1-benzyl-3,4-dimethylhexahydro-1H-1,4-diazepine

The title compound is prepared in substantially the same manner as inExample 108, using 3-benzylamino-2-propanol in place of2-benzylamino-1-propanol in Example 108.

EXAMPLE 110 Preparation of6-benzensulfonylamino-1-benzyl-4-methylhexahydro-1H-1,4-diazepine

A mixture of 1-benzenesulfonyl-2-bromomethylethylenimine (27.2 g),N-benzyl-N'-methylethylenediamine (16.2 g), triethylamine (19.9 g) andchloroform (350 ml) is refluxed with stirring for 5 hours. The solventis evaporated under reduced pressure, and the residue is purified bysilica gel chromatography to give the title compound (7.9 g) as an oil.

EXAMPLE 111

    ______________________________________                                                                 per 1,000                                                                     ampules                                              ______________________________________                                        N-[1-(3-methylbenzyl)-4-methylhexahydro-1H-1,4-                                                          10 g                                               diazepin-6-yl]-1H-indazole-3-carboxamide                                      dihydrochloride                                                               Citric acid                10 g                                               Sorbitol                   50 g                                               Sodium hydroxide           q.s.                                               Water for injection        q.s.                                                                          2000 ml                                            ______________________________________                                    

N-[1-(3-methylbenzyl)-4-methylhexahydro-1H-1,4-diazepin-6-yl]-1H-indazole-3-carboxamidedihydrochloride is dissolved in a sufficient amount of water forinjection, and citric acid and sorbitol are added to the solution. Aftersodium hydroxide is added to the solution to adjust pH value to 4.5,water for injection is added to the solution to give total amount. Theabove solution is filtered by membrane filter (0.22 μm) and the filtrateis filled into 2 ml-ampules, and the ampules are sterilized at 121° C.for 20 minutes.

EXAMPLE 112

    ______________________________________                                                                 per 1,000                                                                     tablets                                              ______________________________________                                        N-[1-(3-fluorobenzyl)-4-methylhexahydro-1H-1,4-                                                         10      g                                           diazepin-6-yl]-1H-indazole-3-carboxamide                                      hemifumarate                                                                  lactose                   76.5    g                                           Corn starch               28      g                                           Microcrystalline cellulose                                                                              25      g                                           Hydroxypropylcellulose    3.5     g                                           Light anhydrous silicic acid                                                                            0.7     g                                           Magnesium stearate        1.3     g                                           ______________________________________                                    

The above components are blended, granulated and made into 1,000 tabletseach weighing 145 mg by a conventional method.

EXAMPLE 113

    ______________________________________                                                                per 1,000                                                                     capsules                                              ______________________________________                                        N-[1-(3-pyridylmethyl)-4-methylhexahydro-1H-                                                            10      g                                           1,4-diazepin-6-yl]-1H-indazole-3-carboxamide                                  5/2 fumarate                                                                  lactose                   190     g                                           Corn starch               22      g                                           Hydroxypropylcellulose    3.5     g                                           Light anhydrous silicic acid                                                                            1.8     g                                           Magnesium stearate        2.7     g                                           ______________________________________                                    

The above components are blended, granulated and filled into 1,000capsules by a conventional method.

EXAMPLE 114

    ______________________________________                                                                 per 1,000 g                                          ______________________________________                                        N-[1-(2-cyanobenzyl)-4-methylhexahydro-1H-1,4-                                                           20     g                                           diazepin-6-yl]-1H-indazole-3-carboxamide                                      oxalate 1/4 hydrate                                                           lactose                    950    g                                           Hydroxypropylcellulose     25     g                                           Light anhydrous silicic acid                                                                             5      g                                           ______________________________________                                    

The above components are blended and made into fine granule by aconventional method.

We claim:
 1. A compound of the formula ##STR85## wherein R₁ and R₂ areidentical or different and each represents(1) hydrogen, (2) a C₁ -C₆alkyl group, (3) a C₁ -C₆ alkyl group substituted by(a) C₃ -C₈cycloalkyl, (b) C₅ -C₈ cycloalkenyl, (c) C₁ -C₆ alkoxy, (d) hydroxy, (e)cyano, (f) oxo, (g) C₂ -C₄ alkanoyloxy, (h) an unsubstituted, mono- ordi-substituted benzoyloxy group said substituent being halogen, C₁ -C₄alkyl, trifluoromethyl, hydroxy, C₁ -C₄ alkoxy, amino, nitro, cyano orcarboxy, (i) amino, (j) mono- or di-C₁ -C₄ alkylamino, (k) C₂ -C₄alkanoylamino, (l) an unsubstituted, mono- or di-substitutedbenzoylamino group the substituent being halogen, C₁ -C₄ alkyl,trifluoromethyl, hydroxy, C₁ -C₄ alkoxy, amino, nitro, cyano or carboxy,(m) a 5 or 6-membered monocyclo- or bicyclo-heteroaromatic group having1 to 2 hetero atoms selected from oxygen and nitrogen, or (n) halogen;(4) a C₃ -C₈ cycloalkyl group, (5) a C₂ -C₆ alkenyl group, (6) a C₅ -C₈cycloalkenyl group, (7) a C₂ -C₆ alkynyl group, (8) a phenyl-C₁ -C₆alkyl group in which the phenyl is unsubstituted or is substituted by(a)halogen, (b) C₁ -C₆ alkyl, (c) trifluoromethyl, (d) hydroxy, (e) C₁ -C₆alkoxy, (f) amino, (g) mono- or di-C₁ -C₆ alkylamino, (h) C₂ -C₆alkanoylamino, (i) an unsubstituted, mono- or di-substitutedbenzoylamino group the said substituent being halogen, C₁ -C₄ alkyl,trifluoromethyl, hydroxy, C₁ -C₄ alkoxy, amino, nitro, cyano or carboxy,(j) nitro, (k) cyano, (l) carboxy or (m) C₂ -C₄ alkoxycarbonyl; (9) a C₂-C₆ alkoxycarbonyl group, (10 ) a phenyl-C₁ -C₆ alkyloxycarbonyl groupin which the phenyl is unsubstituted or is substituted by(a) halogen,(b) C₁ -C₆ alkyl, (c) trifluoromethyl, (d) hydroxy, (e) C₁ -C₆ alkoxy,(f) amino, (g) nitro, (h) cyano or (i) carboxy; (11) a C₂ -C₆ alkanoylgroup, or (12) a benzoyl group which is unsubstituted or is substitutedby(a) halogen, (b) C₁ -C₆ alkyl, (c) trifluoromethyl, (d) hydroxy, (e)C₁ -C₆ alkoxy, (f) amino, (g) nitro, (h) cyano or (i) carboxy; or R₁ andR₂, taken together, form a C₁ -C₆ alkylene group; R₃ represents (1) ahydrogen atom, (2) a C₁ -C₆ alkyl group, or (3) a phenyl group; Z₂represents --NR₆ R₇ in which R₆ represents a hydrogen atom, R₇represents (1) a hydrogen atom, (2) a C₂ -C₆ alkoxycarbonyl group, (3) aphenyl-C₁ -C₆ alkyloxycarbonyl group in which the phenyl isunsubstituted or is substituted by(a) halogen, (b) C₁ -C₆ alkyl, (c)trifluoromethyl, (d) hydroxy, (e) C₁ -C₆ alkoxy, (f) amino, (g) nitro,(h) cyano or (i) carboxy; (4) a C₂ -C₆ alkanoyl group, (5) a benzoylgroup which is unsubstituted or is substituted by(a) halogen, (b) C₁ -C₆alkyl, (c) trifluoromethyl, (d) hydroxy, (e) C₁ -C₆ alkoxy, (f) amino,(g) nitro, (h) cyano or (i) carboxy; (6) a C₁ -C₆ alkylsulfonyl group,(7) a phenylsulfonyl group which may optionally be substituted by(a)halogen, (b) C₁ -C₆ alkyl, (c) trifluoromethyl, (d) hydroxy, (e) C₁ -C₆alkoxy, (f) amino, (g) nitro, (h) cyano or (i) carboxy; or (8) a tritylgroup; or R₆ and R₇, together with the nitrogen atom to which they arebonded, may represent a phthalimide group, m represents 1 or 2, and nrepresents 2, provided that R₁ and R₂ do not simultaneously represent abenzyl group.
 2. A compound of claim 1 whereinR₂ represents (1) ahydrogen atom, (2) a C₁ -C₆ alkyl group,(3) a C₁ -C₆ alkyl groupsubstituted by (a) C₃ -C₈ cycloalkyl, (b) C₅ -C₈ cycloalkenyl, (c) C₁-C₆ alkoxy, (d) hydroxy, (e) oxo, (f) a 5 or 6-membered monocyclo- orbicyclo-heteroaromatic group having 1 to 2 hetero atoms selected fromoxygen and nitrogen, or (g) halogen; (4) a C₃ -C₈ cycloalkyl group, (5)a C₂ -C₆ alkenyl group, (6) a C₅ -C₈ cycloalkenyl group, (7) a C₂ -C₆alkynyl group, (8) a phenyl-C₁ -C₆ alkyl group in which the phenyl isunsubstituted or is substituted by(a) halogen, (b) C₁ -C₆ alkyl, (c)trifluoromethyl, (d) hydroxy, (e) C₁ -C₆ alkoxy, (f) amino, (g) mono- ordi-C₁ -C₆ alkylamino, (h) C₂ -C₆ alkanoylamino, (i) benzoylamino, (j)nitro, (k) cyano, (l) carboxy or (m) C₂ -C₄ alkoxycarbonyl; (9) a C₂ -C₆alkoxycarbonyl group, (10) a phenyl-C₁ -C₆ alkoxycarbonyl group in whichthe phenyl is unsubstituted or is substituted by(a) halogen, (b) C₁ -C₆alkyl, (c) trifluoromethyl or (d) C₁ -C₆ alkoxy; (11) a C₂ -C₆ alkanoylgroup, or (12) a benzoyl group which is unsubstituted or is substitutedby(a) halogen, (b) C₁ -C₆ alkyl, (c) trifluoromethyl or (d) C₁ -C₆alkoxy; R₃ represents (1) a hydrogen atom, or (2) a C₁ -C₆ alkyl group,Z₂ represents --NR₆ R₇ in which R₆ represents a hydrogen atom, and R₇represents (1) a hydrogen atom, (2) a C₂ -C₆ alkoxycarbonyl group, (3) aphenyl-C₁ -C₆ alkyloxycarbonyl group in which the phenyl isunsubstituted or substituted by(a) halogen, (b) C₁ -C₆ alkyl, (c)trifluoromethyl or (d) C₁ -C₆ alkoxy; (4) a C₂ -C₆ alkanoyl group, (5) abenzoyl group which is unsubstituted or is substituted by(a) halogen,(b) C₁ -C₆ alkyl, (c) trifluoromethyl or (d) C₁ -C₆ alkoxy; (6) a C₁ -C₆alkylsulfonyl group, (7) a phenylsulfonyl group which is unsubstitutedor is substituted by(a) halogen, (b) C₁ -C₆ alkyl, (c) trifluoromethylor (d) C₁ -C₆ alkoxy; or (8) a trityl group; or R₆ and R₇, together withthe nitrogen atom to which they are bonded, may represent a phthalimidegroup.
 3. The compound of claim 1 wherein R₁ represents a C₁ -C₆ alkylgroup.
 4. The compound of claim 2 whereinR₂ represents a hydrogen atom,a C₁ -C₆ alkyl group, a C₁ -C₆ alkyl group substituted byC₃ -C₆cycloalkyl, C₅ -C₆ cycloalkenyl, or 5 or 6 membered monocyclo- orbicyclo-heteroaromatic having 1 to 2 heteroatoms selected from oxygenand nitrogen atoms; a C₅ -C₆ cycloalkyl group, an allyl group, or aphenyl-C₁ -C₄ alkyl group in which the phenyl is unsubstituted or ismono- or di-substituted byhalogen, C₁ -C₄ alkyl, trifluoromethyl, C₁ -C₄alkoxy, nitro or cyano; and m represents a number of
 1. 5. The compoundof claim 4 wherein R₁ represents a C₁ -C₄ alkyl group,R₂ represents ahydrogen atom, a C₁ -C₄ alkyl group, a pyridylmethyl group, or a benzylgroup which is unsubstituted or is mono- or di-substituted byhalogen, C₁-C₄ alkyl, trifluoromethyl, C₁ -C₄ alkoxy or cyano; R₃ represents ahydrogen atom, or a C₁ -C₄ alkyl group, Z₂ represents --NR₆ R₇ is whichR₆ represents a hydrogen atom, and R₇ represents a hydrogen atom, a C₂-C₄ alkoxycarbonyl group, a benzyloxycarbonyl group which isunsubstituted or is mono- or di-substituted byhalogen, C₁ -C₄ alkyl,trifluoromethyl, or C₁ -C₄ alkoxy; a C₂ -C₄ alkanoyl group, a benzoylgroup which is unsubstituted or is mono- or di-substituted byhalogen, C₁-C₄ alkyl, trifluoromethyl or C₁ -C₄ alkoxy; a C₁ -C₄ alkylsulfonylgroup, a phenylsulfonyl group which is unsubstituted or ismono-substituted byhalogen, C₁ -C₄ alkyl, trifluoromethyl or C₁ -C₄alkoxy; or a trityl group; or R₆ and R₇, together with the nitrogen atomto which they are bonded, may represent a phthalimide group.
 6. Thecompound of claim 5 wherein R₁ represents a methyl group or an ethylgroup,R₂ represents a hydrogen atom, a methyl group, an ethyl group, apyridylmethyl group, a benzyl group, a methylbenzyl group, afluorobenzyl group, a chlorobenzyl group, a bromobenzyl group, atrifluorobenzyl group, a methoxybenzyl group, a cyanobenzyl group, adifluorobenzyl group, or a dimethylbenzyl group, R₃ represents ahydrogen atom, or a methyl group, Z₂ represents --NR₆ R₇ in which R₆represents a hydrogen atom, and R₇ represents a hydrogen atom, amethoxycarbonyl group, a ethoxycarbonyl group, a benzyloxycarbonylgroup, a methylbenzyloxycarbonyl group, a methoxylbenzyloxycarbonylgroup, an acetyl group, a propionyl group, a benzoyl group, amethylbenzoyl group, a methoxybenzoyl group, a methylsulfonyl group, anethylsulfonyl group, a phenylsulfonyl group, a methylphenylsulfonylgroup, or a trityl group, or R₆ and R₇, together with the nitrogen atomto which they are bonded, may represent a phthalimide group.
 7. Acompound represented by the formula (III') ##STR86## wherein R₁represents hydrogen or C₁ -C₆ alkyl,R₂ represents(1) hydrogen; (2) C₁-C₆ alkyl; (3) C₁ -C₆ alkyl substituted by (a) C₃ -C₆ cycloalkyl, (b) C₅-C₆ cycloalkenyl, or (c) 5- or 6-membered monocyclo- orbicyclo-heteroaromatic having 1 or 2 hetero atoms selected from oxygenand nitrogen atoms; (4) C₅ -C₆ cycloalkyl; (5) allyl; or (6) phenyl-C₁-C₄ alkyl in which the phenyl is unsubstituted or is mono- ordi-substituted by halogen, C₁ -C₄ alkyl, trifluoromethyl, C₁ -C₄ alkoxy,nitro or cyano, R₃ represents hydrogen or C₁ -C₆ alkyl, Z₂ represents--NR₆ R₇ in which R₆ represents hydrogen, R₇ represents(1) hydrogen; (2)acetyl; (3) ethoxycarbonyl; (4) benzyloxycarbonyl; (5) benzenesulfonyl;or (6) 4-methylphenylsulfonyl; or R₆ and R₇, together with the nitrogenatom to which they are bonded, may represent phthalimide, m represents1, and n represents
 2. 8. A compound of claim 7 in which R₇ representshydrogen.
 9. A compound of claim 7 in which R₇ represents acetyl.
 10. Acompound represented by the formula (III') ##STR87## wherein R₁represents alkyl having 1 to 4 carbon atoms,R₂ represents hydrogen,alkyl having 1 to 4 carbon atoms, pyridylmethyl; or benzyl which isunsubstituted or is mono- or di-substituted by halogen, C₁ -C₄ alkyl,trifluoromethyl, C₁ -C₄ alkoxy or cyano, R₃ represents hydrogen or C₁-C₄ alkyl, Z₂ represents --NR₆ R₇ in which R₆ represents hydrogen, R₇represents(1) hydrogen; (2) acetyl; (3) ethoxycarbonyl; (4)benzyloxycarbonyl; (5) benzenesulfonyl; or (6) 4-methylphenylsulfonyl;or R₆ and R₇, together with the nitrogen atom to which they are bonded,may represent phthalimide, m represents 1, and n represents
 2. 11. Acompound of claim 10 in which R₇ represents hydrogen.
 12. A compound ofclaim 10 in which R₇ represents acetyl.
 13. A compound of claim 10 inwhich R₁ represents methyl or ethyl,R₂ represents methyl, ethyl, benzyl,methylbenzyl, fluorobenzyl, chlorobenzyl, bromobenzyl,trifluoromethylbenzyl, methoxybenzyl, cyanobenzyl, difluorobenzyl,dimethylbenzyl or pyridylmethyl, R₃ represents hydrogen or methyl, Z₂represents --NR₆ R₇ in which R₆ represents hydrogen, and R₇represents(1) hydrogen; (2) acetyl; (3) ethoxycarbonyl; (4)benzyloxycarbonyl; (5) benzenesulfonyl; or (6) 4-methylphenylsulfonyl;or R₆ and R₇, together with the nitrogen atom to which they are bonded,may represent phthalimide.
 14. A compound of claim 13 in which R₇represents hydrogen.
 15. A compound of claim 13 in which R₇ representsacetyl.
 16. A compound selected from the group consisting of(1)6-acetylamino-1-benzyl-4-methylhexahydro-1H-1,4-diazepine, (2)6-acetylamino-1-(3-methylbenzyl)-4-methylhexahydro-1H-1,4-diazepine, (3)6-acetylamino-1-(3-fluorobenzyl)-4-methylhexahydro-1H-1,4-diazepine, (4)6-acetylamino-1-(4-cyanobenzyl)-4-methylhexahydro-1H-1,4-diazepine, (5)6-acetylamino-1-(3-cyanobenzyl)-4-propylhexahydro-1H-1,4-diazepine, (6)6-acetylamino-1-(3,5-difluorobenzyl)-4-methylhexahydro-1H-1,4-diazepine,(7)6-acetylamino-1-(3-pyridylmethyl)-4-methylhexahydro-1H-1,4-diazepine,(8) 6-acetylamino-1,4-dimethylhexahydro-1H-1,4-diazepine, (9)6-acetylamino-1,4-diethylhexahydro-1H-1,4-diazepine, (10)6-benzenesulfonylamino-1-benzyl-2,4-dimethylhexahydro-1H-1,4-diazepine,(11)6-benzyloxycarbonylamino-1-(3-methylbenzyl)-4-methylhexahydro-1H-1,4-diazepine,(12) 6-ethoxycarbonylamino-1-benzyl-4-methylhexahydro-1H-1,4-diazepine,(13)6-(4-methylphenyl)sulfonylamino-1,4-dimethylhexahydro-1H-1,4-diazepine,an (14)N-(1-benzyl-4-methylhexahydro-1H-1,4-diazepine-6-yl)-phthalimide.